Long-term non-invasive and continuous measurements of legume nodule activity.

Symbiotic nitrogen fixation is a process of considerable economic, ecological and scientific interest. The central enzyme nitrogenase reduces H(+) alongside N2 , and the evolving H2 allows a continuous and non-invasive in vivo measurement of nitrogenase activity. The objective of this study was to show that an elaborated set-up providing such measurements for periods as long as several weeks will produce specific insight into the nodule activity's dependence on environmental conditions and genotype features. A system was developed that allows the air-proof separation of a root/nodule and a shoot compartment. H2 evolution in the root/nodule compartment can be monitored continuously. Nutrient solution composition, temperature, CO2 concentration and humidity around the shoots can concomitantly be maintained and manipulated. Medicago truncatula plants showed vigorous growth in the system when relying on nitrogen fixation. The set-up was able to provide specific insights into nitrogen fixation. For example, nodule activity depended on the temperature in their surroundings, but not on temperature or light around shoots. Increased temperature around the nodules was able to induce higher nodule activity in darkness versus light around shoots for a period of as long as 8 h. Conditions that affected the N demand of the shoots (ammonium application, Mg or P depletion, super numeric nodules) induced consistent and complex daily rhythms in nodule activity. It was shown that long-term continuous measurements of nodule activity could be useful for revealing special features in mutants and could be of importance when synchronizing nodule harvests for complex analysis of their metabolic status.

Elevated resting heart rate, physical fitness and all-cause mortality: a 16-year follow-up in the Copenhagen Male Study.

OBJECTIVE: To examine whether elevated resting heart rate (RHR) is an independent risk factor for mortality or a mere marker of physical fitness (VO2Max). METHODS: This was a prospective cohort study: the Copenhagen Male Study, a longitudinal study of healthy middle-aged employed men. Subjects with sinus rhythm and without known cardiovascular disease or diabetes were included. RHR was assessed from a resting ECG at study visit in 1985-1986. VO2Max was determined by the Åstrand bicycle ergometer test in 1970-1971. Subjects were classified into categories according to level of RHR. Associations with mortality were studied in multivariate Cox models adjusted for physical fitness, leisure-time physical activity and conventional cardiovascular risk factors. RESULTS: 2798 subjects were followed for 16 years. 1082 deaths occurred. RHR was inversely related to physical fitness (p < 0.001). Overall, increasing RHR was highly associated with mortality in a graded manner after adjusting for physical fitness, leisure-time physical activity and other cardiovascular risk factors. Compared to men with RHR ≤ 50, those with RHR > 90 had an HR (95% CI) of 3.06 (1.97 to 4.75). With RHR as a continuous variable, risk of mortality increased with 16% (10-22) per 10 beats per minute (bpm). There was a borderline interaction with smoking (p = 0.07); risk per 10 bpm increase in RHR was 20% (12-27) in smokers, and 14% (4-24) in non-smokers. CONCLUSIONS: Elevated RHR is a risk factor for mortality independent of physical fitness, leisure-time physical activity and other major cardiovascular risk factors.

Occupational noise exposure, social class, and risk of ischemic heart disease and all-cause mortality--a 16-year follow-up in the Copenhagen Male Study.

OBJECTIVE: Long-term exposure to occupational noise may be associated with an increased risk of ischemic heart disease (IHD) and all-cause mortality. However, the issue remains unsettled. Only a small number of longitudinal studies have been carried out, and control for potential confounders including a strong correlate of noise exposure namely social class may have been insufficient. METHODS: We carried out a 16-year follow-up of 2998 men aged 53-75 years without overt cardiovascular disease. RESULT: Overall, 197 men (6.6%) died due to IHD and 1192 (39.8%) from all-causes. Of the 2998 men, 1008 (33.6%) reported exposure to occupational noise for ≥5 years [mean 25.4, standard deviation (SD) 12.5 years]; among these men, 47.3% reported hearing impairment versus only 24.8% among unexposed men (63.0%). Referencing unexposed men, the hazard ratio (HR) for IHD mortality was 0.97 [95% confidence interval (95% CI) 0.71-1.33], and the HR for all-cause mortality was 1.01 (95% CI 0.89-1.15) when adjusting for potential confounders: age, hearing impairment, blood pressure, diabetes, fasting serum triglycerides and high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, glucosuria, cancer, body mass index, alcohol, tobacco, leisure-time physical activity, and social class. Stratified analyses of high and low social classes confirmed the overall results. CONCLUSION: Cumulative occupational exposure to noise was strongly associated with hearing impairment, but not with death from either IHD or all-cause mortality in a long-term follow-up adjusting for established cardiovascular risk factors including low social class.

Serum selenium level and risk of lung cancer mortality: a 16-year follow-up of the Copenhagen Male Study.

Serum selenium has been implicated as a risk factor for lung cancer, but the issue remains unsettled. In a cohort of 3,333 males aged 53-74 yrs, we tested the hypothesis that a low serum selenium concentration would be associated with an increased risk of lung cancer mortality. Over 16 yrs, 167 (5.1%) subjects died of lung cancer: 48 (5.0%) out of 965 with low serum selenium (0.4-1.0 µmol · L(-1)), 57 (5.1%) out of 1,141 with medium serum selenium (1.1-1.2 µmol · L(-1)) and 62 (5.1%) out of 1,227 with high serum selenium (1.3-3.0 µmol · L(-1)). After adjustment for age, referencing the lowest level of serum selenium, hazard ratios (HRs) for medium and high levels of serum selenium were 0.97 (95% CI 0.66-1.43) and 0.99 (95% CI 0.68-1.45), respectively. Taking into account pack-years of smoking, spirits intake, dietary markers (salt and fat preferences) and health measures (chronic bronchitis and peak flow), referencing the lowest level of serum selenium, HRs were 1.17 (95% CI 0.79-1.75) and 1.43 (95% CI 0.96-2.14), for medium and high levels respectively. Among heavy smokers, a high serum selenium concentration was associated with a significantly increased risk of lung cancer mortality after taking into account all potential confounders. The hypothesis that low serum selenium is an independent risk factor for lung cancer was not supported.

Determinants of obesity among men with the lewis double-negative blood group: a genetic marker of obesity-the Copenhagen Male Study.

OBJECTIVE: Middle-aged and elderly men with the Lewis blood group phenotype Le(a-b-), have a two-fold higher prevalence of obesity than others. We investigated if the association could be ascribed to differences in lifestyle, or if obesity determinants had a different impact in this group. METHOD: This was a cross-sectional study of 3,290 men aged 53-74 years with a mean of 63 years drawn from the Copenhagen Male Study. The main outcome measure was prevalence of obesity [body mass index (BMI) ≥30 (kg/m(2))]. RESULTS: Among men with the Le(a-b-) phenotype (n = 315), the prevalence of obesity was 15.6%; it was 8.1% among men with other phenotypes (n = 2,975, p < 0.001). Obesity-related life style habits did not differ between Le(a-b-) and other men. In multiple logistic regression analyses, the role of obesity covariates was conspicuously different between men with the Le(a-b-) phenotype and men with other Lewis phenotypes. However, among Le(a-b-) men, a much stronger inverse association was found between high coffee consumption (>7 cups/day vs. less) and obesity, and between lacking fat avoidance and obesity; the odds ratio [95% confidence interval (CI)] for high coffee consumption was 0.2(0.1-0.7) and for avoidance of fatty foods 2.0(1.04-3.7). The association of obesity with leisure time physical activity, smoking, alcohol use, use of sugar in hot beverages, and tea consumption, did not differ between Le(a-b-) men and others. CONCLUSIONS: Our findings suggests a gene-environment interaction between lifestyle and obesity. Because some ethnic groups have up to 40% with the Le(a-b-) phenotype, the above observations may be of significant public health interest.

Antihypertensive treatment, high triglycerides, and low high-density lipoprotein cholesterol and risk of ischemic heart disease mortality: a 16-year follow-up in the Copenhagen male study.

OBJECTIVE: The aim of this study was to test the hypothesis that metabolic syndrome dyslipidemia is a major risk factor for ischemic heart disease (IHD) mortality among men taking antihypertensive medication. METHODS: This was a 16-year follow up of 2,986 men 53-75 years old without overt cardiovascular disease; 357 men used antihypertensive medicine. Potential risk factors were type of baseline medication, blood pressure, diabetes, fasting serum triglycerides (TG), high-density lipoprotein (HDL-C) and total cholesterol, glucosuria, electrocardiogram (ECG) changes, cancer history, body mass index, alcohol and tobacco use, leisure time physical activity, social class, and age. The main outcome was IHD mortality. RESULTS: Men treated for hypertension had a two-fold higher cumulative incidence of IHD mortality during the follow up compared to other men (12.0% vs, 5.8%). Dyslipidemia was defined as TG >or=1.70 mmol/L or HDL-C

Sugar in coffee or tea and risk of obesity: A neglected issue.

AIM: In the Copenhagen Male Study sugar intake in coffee or tea is inversely associated with obesity. We analyzed the association of sugar intake with obesity among men with and without lifestyle factors indicating health awareness. METHODS: A cross-sectional study of 3,290 men aged 53-75 years including information about smoking, alcohol, physical activity, tea and coffee use, avoidance of fatty food, social class, self-assessed health, and family obesity. RESULTS: Overall, 291 men (8.8%) were obese, body mass index > or =30. Among men using sugar in coffee or tea (36%), the prevalence was 6.2%; among others, 10.3% (odds ratio [95% confidence interval]=0.6 [0.4-0.8]). An inverse association between use of sugar in hot beverages and prevalence of obesity was consistent in subgroups, and most pronounced among the least health-conscious [odds ratio [95% confidence interval]=0.4 [0.2-0.8]). INTERPRETATION: The results indicate a weight-controlling or reducing effect of small amounts of sucrose ingested several times a day.

Metabolic and lifestyle predictors of ischemic heart disease and all-cause mortality among normal weight, overweight, and obese men: a 16-year follow-up in the Copenhagen Male Study.

AIM: The aim of this study was to identify metabolic and lifestyle risk factors for ischemic heart disease (IHD) and all-cause mortality (ACM) among normal weight, overweight, and obese men. METHODS: This was a 16-year follow up of 2982 men 53 to 75 years without overt cardiovascular disease. POTENTIAL RISK FACTORS: These were blood pressure, diabetes, fasting serum triglycerides (TGs) and high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), glucosuria, cancer, body mass index (BMI), alcohol, tobacco, leisure-time physical activity, social class, and age. MAIN OUTCOME: This was to determine mortality during 16 years of follow-up. RESULTS: A total of 194 men (6.5%) died due to IHD and 1184 (39.8%) from all causes. All lifestyle factors and clinical/metabolic risk factors were associated with BMI, positively or negatively. Risk of IHD and ACM increased gradually from the normal weight (BMI 20.0-25.0) to higher BMI groups. With respect to IHD, compared to normal weight men, obese men (BMI > or = 30.0) had an age-adjusted hazard ratio (HR) (95%CI) of 1.67(1.04-2.68); adjusted for potential confounders HR was 0.99 (0.59-1.66); corresponding estimates for ACM were 1.21 (0.98-1.49) and 0.86 (0.68-1.09). High TG (>1.70 mmol/L) was an independent risk factor for IHD mortality only among men with BMI < or = 27.5 kg/m(2); low HDL-C (< or =1.03 mmol/L) was an independent risk factor for IHD mortality only among men with BMI > 27.5 kg/m(2). Cumulative smoking and type 2 diabetes/glucosuria were the strongest risk factors of ACM among men with a BMI < or = 27.5 as well as men with a BMI > 27.5. CONCLUSION: The importance of risk factors for IHD mortality, in particular serum TG and serum HDL-C, depends on BMI.

Wine intake, ABO phenotype, and risk of ischemic heart disease and all-cause mortality: the Copenhagen Male Study--a 16-year follow-up.

The association of alcohol intake with ischemic heart disease (IHD) and all-cause mortality may depend on ABO phenotype. We tested this hypothesis in a 16-year follow-up of 3,022 Caucasian men aged 53-74 years without overt cardiovascular disease. Potential risk factors and confounders included were ABO phenotypes, alcohol intake (wine, beer, and spirits), tobacco smoking history, leisure-time physical activity, social class, and age. During 16 years, 1985-1986 to end of 2001, 197 subjects (6.5%) died due to IHD, and 1,204 (39.8%) from all causes. Among non-O phenotypes (A, B, and AB) significantly fewer men who died due to IHD were wine consumers, 43.9% versus 55.7%, P<.01; with respect to all-cause mortality corresponding figures were 47.0% versus 60.1%, P<.001. No difference was found among men with phenotype O. Among men with phenotype A, compared to alcohol abstainers, in Cox analysis, the hazard ratio (HR) (95% confidence limit) for men drinking up to 8 beverages/wk was 0.5 (0.3-1.02), and among men consuming >8 beverages/wk (the highest quintile) the HR was 0.3 (0.2-0.8), P<.01. Among men with phenotype O, the association of wine intake with IHD mortality was slightly and not significantly U-shaped. The difference in the predictive role of wine intake between phenotype O and phenotype A men was supported in a statistical test for interaction. A similar association was found for all-cause mortality. The results suggest that the effect of wine intake on IHD and all-cause mortality among middle-aged and elderly men may depend on ABO phenotypes.

Occupational organic solvent exposure, smoking, and prevalence of chronic bronchitis-an epidemiological study of 3387 men.

OBJECTIVE: To investigate the interaction of smoking and history of long-term occupational exposure to organic solvents on the prevalence of chronic bronchitis (CB) among middle aged and elderly men. METHODS: A questionnaire on health, lifestyle, and working conditions, and a clinical examination including measurements of height, weight, and peak-flow. Self-reported occupational solvent exposure for 5 years or more was compared to never exposed. Three thousand two hundred eight men aged 63 +/- 10 years were included. RESULTS: Four hundred sixty one men had CB (14.4%). Current smoking and the interaction of smoking and long-term occupational exposure to organic solvents (> 5 years) were the factors most strongly associated with prevalence of CB. In the solvent exposed group odds ratio for CB was 7.0 (95% confidence interval [CI]: 3.4 to 14.5) comparing current smokers with non-smokers against only 3.7 (95% CI: 2.8 to 4.8) in the nonexposed group, also after control for potential confounders. Among nonsmokers only, long-term exposure to organic solvents was not associated with an increased prevalence of CB. CONCLUSION: Current or previous occupational exposure to organic solvents doubles the smoking related risk of CB, probably due to an additional irritative effect in the alveolar and bronchial mucosa.

Preservation of microelastic properties of dentin and tooth enamel in vitro--a scanning acoustic microscopy study.

OBJECTIVES: The aim of this study was to examine the influence of storage media on the elastic properties of dentin and tooth enamel with respect to the storage period. Several reports suggest that saline and other aqueous solutions may induce chemical reactions and the dissolution of minerals, which in turn may cause alterations of elastic tissue properties. METHODS: Three non-erupted human wisdom teeth were extracted and divided in three slices. Sections were stored in three different media for a maximum period of 21 days. During this time all sections were inspected by time-resolved 50-MHz scanning acoustic microscopy. RESULTS: Storage in saline solution resulted in a progressive decrease of the acoustic impedance up to 70% in dentin but not in enamel tissue. Hank's balanced salts solution and artificial saliva appeared to maintain the elastic properties of dentin and enamel during the entire time of storage. The measurements of surface wave velocities did not show significant differences. High resolution (900 MHz) inspection of sections cut perpendicular to the surface exposed to the storage media for 21 days revealed a progressive increase of impedance in dentin up to the initial values at a depth of approximately 300 microm. SIGNIFICANCE: These findings suggest that quantitative SAM is a suitable tool for assessing surface and sub-superficial elastic properties of tooth tissue.

Increased ventricular ectopic activity in relation to C-reactive protein, and NT-pro-brain natriuretic peptide in subjects with no apparent heart disease.

BACKGROUND: Subjects with frequent ventricular premature complexes (VPC) and no apparent heart disease make a heterogenic group with regard to prognosis. Some biomarkers have recently proved useful in risk stratification in different heart diseases. We examined prognostic impact of NT-Pro-brain natriuretic peptide (NT-Pro BNP), and C-reactive protein (CRP) in relation to frequent VPC in subjects with no apparent heart disease. METHODS: Six hundred seventy-eight healthy subjects between 55 and 75 years of age with no history of cardiovascular disease were included in the study. All were tested with fasting laboratory testing and 48-hour ambulatory ECG monitoring. Frequent VPC was defined as VPC > or =30/hour. RESULTS: In 56 subjects (8%) with frequent VPC the prognosis was much poorer compared to those without frequent VPC (Hazard ratio and 95% CI: 2.3;1.2-4.4, P = 0.01), after adjustment for conventional risk factors. In subjects with frequent VPC increased levels of CRP (above 2.5 microg/mL) was the only factor among the tested biomarkers, which was associated with a poor prognosis. Taking subjects without frequent VPC as reference, the hazard ratio and 95% CI for subjects with frequent VPC and increased CRP was 3.6;1.8-7.1, P = 0.0004, and for those with frequent VPC and normal CRP 0.8;0.2-3.5, P = 0.83, after correction for conventional risk factors. CONCLUSIONS: Among middle-aged and elderly subjects with no apparent heart disease and frequent VPCs, a CRP value > or =2.5 microg/mL is associated with a significantly higher risk of death and acute myocardial infarction. These subjects deserve primary prevention measures and further work up for structural heart disease.

Effect of tumor therapeutic irradiation on the mechanical properties of teeth tissue.

Tumor irradiation of the head-neck area is accompanied by the development of a so-called radiation caries in the treated patients. In spite of conservative therapeutic measures, the process results in tooth destruction. The present study investigated the effects of irradiation on the demineralization and remineralization of the dental tissue. For this purpose, retained third molars were prepared and assigned either to a test group, which was exposed to fractional irradiation up to 60 Gy, or to a non-irradiated control group. Irradiated and non-irradiated teeth were then demineralized using acidic hydroxyl-cellulose gel; afterwards the teeth were remineralized using either Bifluorid12 or elmex gelee. The nanoindentation technique was used to measure the mechanical properties, hardness and elasticity, of the teeth in each of the conditions. The values were compared to the non-irradiated control group. Irradiation decreased dramatically the mechanical parameters of enamel and dentine. In nonirradiated teeth, demineralization had nearly the same effects of irradiation on the mechanical properties. In irradiated teeth, the effects of demineralization were negligible in comparison to non-irradiated teeth. Remineralization with Bifluorid12 or elmex gelee led to a partial improvement of the mechanical properties of the teeth. The enamel was more positively affected by remineralization than the dentine.

Ventricular arrhythmias and risk of death and acute myocardial infarction in apparently healthy subjects of age >or=55 years.

Increased ventricular ectopic activity and even more complex arrhythmias are not uncommon in subjects without apparent heart disease. However, their prognostic significance has been controversial and not updated in recent years. The prevalence and prognostic significance of different ventricular arrhythmias were studied in a cohort of middle-aged and elderly subjects without apparent heart disease. Six hundred seventy-eight men and women aged 55 to 75 years without a history of heart disease or stroke were included. Baseline examinations included physical examinations, fasting laboratory testing, and 48-hour ambulatory electrocardiographic monitoring. All patients were followed for up to 5 years. Combined events were defined as all-cause mortality or acute myocardial infarction. A cardiovascular event was defined as cardiovascular death or acute myocardial infarction. In total, 84% had 0 to 10 ventricular premature complexes (VPCs)/hour, 8% had 11 to 30 VPCs/hour, and 8% had >30 VPCs/hour; 10.8% had >or=1 run of >or=3 VPCs. Frequent VPCs (>or=30/hour) was a significant predictor of combined (hazard ratio 2.47, 95% confidence interval 1.29 to 4.68, p = 0.006) and cardiovascular (hazard ratio 2.85, 95% confidence interval 1.16 to 7.0, p = 0.023) event rates, after adjustment for conventional risk factors. Runs of >or=4 VPCs/day or >or=2 doublets/day were also associated with a poor prognosis, but only in the presence of frequent VPCs. The detection of a single VPC on standard electrocardiography was a significant predictor of frequent VPCs and an independent predictor of events (hazard ratio 2.6, 95% confidence interval 1.02 to 6.66, p = 0.045). In conclusion, apparently healthy, middle-aged and elderly subjects with frequent VPCs (>or=30/hour) have a poor prognosis. According to current guidelines, strict risk-factor modification and primary prevention are justified in these high-risk subjects.

Physical activity in leisure-time and risk of cancer: 14-year follow-up of 28,000 Danish men and women.

AIM: The preventive effect of physical activity on risk of cancer in general remains controversial. This study aimed at assessment of the associations between leisure- time physical activity and incidence of cancer in the general population of adult men and women. METHODS: 13,216 women and 18,718 men aged 20-93 years selected from the general population participated in a health examination including a questionnaire with information on physical activity, smoking, alcohol intake, postmenopausal hormones, and socioeconomic status. Incident cases of cancers where recorded during a follow-up period of 14 years. The six most frequent cancer cases in both sexes were included in this analysis. RESULTS: A highly significant inverse association was seen between vigorous physical activity in leisure time and cancer of the ovary, adjusted rate ratio being 0.33 (95% CI 0.16-0.67; p = 0.001) for the most physical active women. In men there was a highly significant increase for non-melanoma skin cancer, with adjusted rate ratio of 1.72 (95% CI 1.23-2.40; p = 0.001), for the most active men and vigorous activity was associated with a non-significant lower risk of colon cancer, the adjusted rate ratio being 0.72 (95% CI 0.47-1.11; p = 0.06). CONCLUSION: Generally, there were no, or only weakly, inverse associations between physical activity in leisure time and incidence of cancer, except for cancer of the ovary.

Prevalence and prognostic significance of daily-life silent myocardial ischaemia in middle-aged and elderly subjects with no apparent heart disease.

AIMS: We aimed to determine the prevalence and prognostic significance of daily-life silent myocardial ischaemia (SMI) in healthy middle-aged and elderly subjects with no previous heart disease. METHODS AND RESULTS: Six hundred and seventy-eight healthy men and women between 55 and 75 years of age and with no history of cardiovascular disease or stroke were included. Baseline examinations included physical examination, fasting laboratory testing, and 48 h ambulatory electrocardiogram monitoring. An episode of ischaemia was defined by a down-sloped or horizontal ST depression of at least 1 mm at a duration of at least 1 min. Seventy-seven subjects (11.4%) had SMI. All participants were followed for up to 5 years. In 77 subjects with SMI, 16 (20.7%) had an event (death or myocardial infarction). In 601 subjects without SMI, 50 (8.3%) had an event. The hazard ratios for SMI in relation to cardiac and combined events after correction for conventional risk factors were 3.1 [(1.24-7.97), P=0.016] and 1.97 [(1.06-3.69), P=0.033], respectively. CONCLUSION: SMI as detected by Holter monitoring was detected in 11.4% of these subjects and was associated with more than three-fold increase in the cardiac event rate after correction for risk factors, implying that this test could be used to identify high-risk individuals among these subjects.

Changes in alcohol intake and mortality: a longitudinal population-based study.

BACKGROUND: Using alcohol intake at one point in time, numerous studies have shown a J- or U-shaped relation with all-cause mortality. Mortality is lowest among the light to moderate drinkers, with the risk of dying from coronary heart disease higher among nondrinkers and the risk of dying from cancer higher among heavy drinkers. We studied whether changes in individual alcohol intake result in corresponding changes in mortality. METHODS: In a longitudinal study of 6644 men and 8010 women, age 25 to 98 years, who had attended at least 2 health surveys with a 5-year interval between them, we addressed the risk of death after combinations of changes in alcohol intake. RESULTS: Mortality after changes in alcohol intake was consistent with the mortality observed among those who reported stable drinking. Stable drinkers showed a U-shaped all-cause mortality, with relative risks of 1.29 (95% confidence interval [CI] = 1.13-1.48) for nondrinkers (< 1 drink per week) and 1.32 (1.15-1.53) for heavy drinkers (> 13 drinks per week) compared with light drinkers (1 to 6 drinks per week). For coronary heart disease mortality, stable nondrinkers had a relative risk of 1.32 (0.97-1.79) compared with stable light drinkers and those who had reduced their drinking from light to none increased their risk (1.40; 1.00-1.95), and those who had increased from nondrinking to light drinking reduced their relative risk ratio (0.71; 0.44-1.14). Cancer mortality was increased in all groups of heavy drinkers. CONCLUSION: Persons with stable patterns of light and moderate alcohol intake had the lowest all-cause mortality. Individual changes in alcohol intake were followed by corresponding changes in mortality.

Increased heart rate and reduced heart-rate variability are associated with subclinical inflammation in middle-aged and elderly subjects with no apparent heart disease.

AIM: Elevation of inflammation markers, high heart rate, and reduced heart-rate variability are all strong markers of mortality in a broad spectrum of patients. The association between these markers has not been clarified thoroughly. We investigated the associations between markers of inflammation, heart rate, and heart-rate variability. METHODS AND RESULTS: Six hundred and forty-three healthy men and women between 55 and 75 years of age and with no prior history of cardiovascular disease or stroke were included in the study. The baseline study included a physical examination, fasting laboratory tests, and 24-h ambulatory ECG monitoring. We selected the time-domain components of heart-rate variability for further analyses. C-reactive protein concentration and white blood cell count were selected as markers of inflammation. After identifying parameters related to measures of heart-rate variability, we used regression analyses to evaluate independent associations. Heart-rate variability, as measured by the standard deviation of the time between normal-to-normal complexes or the standard deviation of the average of normal-to-normal intervals for each 5-min period, was negatively associated with smoking, C-reactive protein, white blood cell count, blood sugar and triglyceride concentration, female gender, and diabetes. In contrast, physical activity was strongly associated with higher heart-rate variability. In multivariate regression analyses, increased heart-rate and reduced heart-rate variability were significantly and independently related to white blood cell count or C-reactive protein concentration. CONCLUSION: Increased heart rate and reduced heart-rate variability are associated with subclinical inflammation in healthy middle-aged and elderly subjects. The increased mortality that has been reported in these settings may thus have a common aetiology. An autonomic imbalance in favour of the sympathetic system may interact with inflammatory processes to play a more important role in the process of atherosclerosis than previously thought.