Association between social isolation and inflammatory markers in depressed and non-depressed individuals: results from the MONICA/KORA study

Introduction

Depressed individuals not only suffer from chronic low grade inflammation, but also exhibit an inflammatory hyper-responsiveness to acute stress. We investigate whether chronic stress also induces an exaggerated inflammatory response in individuals with increased depression features. As model for chronic stress, social isolation was chosen.

Methods

Interleukin (IL)-6 and hs-CRP levels were assessed in 1547 subjects (847 men and 700 women), derived from the population-based MONICA/KORA study. Standardized questionnaires were used to assess depressed mood (depression and exhaustion subscale) and social isolation (social network index). The relationship between the two inflammatory markers, social isolation and depressed mood was examined taking into account interactions social isolation × depressed mood using multivariable linear regression models, adjusted for age, BMI, smoking, alcohol, and physical activity. Analyses were performed in men and women separately.

Results

We observed a significant interaction between depressed mood and social isolation regarding IL-6 and hs-CRP, respectively in men (p-value = 0.02 for IL-6 and <0.01 for hs-CRP), evidencing a substantial synergistic effect of social isolation, and depressed mood on inflammatory responses. Furthermore, depressed and socially isolated men had highly significantly elevated IL-6 levels (geometric mean: 3.76 vs. 1.92 pg/ml, p-value <0.01) and heightened hs-CRP levels (geometric mean: 2.01 vs. 1.39 mg/l, p = 0.08) in comparison with non-depressed and socially integrated men. In women, no significant associations were seen.

Conclusion

The interaction of depressed mood and social isolation elicits a substantial synergistic impact on inflammatory markers in men, but not in depressed women.     

Prevalence and risk factors of sexual dysfunction in men and women

Sexual dysfunctions are highly prevalent, affecting about 43% of women and 31% of men. Hypoactive sexual desire disorder has been reported in approximately 30% of women and 15% of men in population-based studies, and is associated with a wide variety of medical and psychologic causes. Sexual arousal disorders, including erectile dysfunction in men and female sexual arousal disorder in women, are found in 10% to 20% of men and women, and is strongly age-related in men. Orgasmic disorder is relatively common in women, affecting about 10% to 15% in community-based studies. In contrast, premature ejaculation is the most common sexual complaint of men, with a reporting rate of approximately 30% in most studies. Finally, sexual pain disorders have been reported in 10% to 15% of women and less than 5% of men. In addition to their widespread prevalence, sexual dysfunctions have been found to impact significantly on interpersonal functioning and overall quality of life in both men and women.     

Prevalence and risk factors of sexual dysfunction in men and women

Sexual dysfunctions are highly prevalent, affecting about 43% of women and 31% of men. Hypoactive sexual desire disorder has been reported in approximately 30% of women and 15% of men in population-based studies, and is associated with a wide variety of medical and psychologic causes. Sexual arousal disorders, including erectile dysfunction in men and female sexual arousal disorder in women, are found in 10% to 20% of men and women, and is strongly age-related in men. Orgasmic disorder is relatively common in women, affecting about 10% to 15% in community-based studies. In contrast, premature ejaculation is the most common sexual complaint of men, with a reporting rate of approximately 30% in most studies. Finally, sexual pain disorders have been reported in 10% to 15% of women and less than 5% of men. In addition to their widespread prevalence, sexual dysfunctions have been found to impact significantly on interpersonal functioning and overall quality of life in both men and women.     

Plasma levels of free and total TFPI, relationship with cardiovascular risk factors and endothelial cell markers.

Free-TFPI (f-TFPI) presents high anticoagulant activity and its plasma level correlates with unfavorable outcomes in unstable angina. Total TFPI (t-TFPI) represents mainly the lipid-bound form which seems to have a poor anticoagulant activity. Until now, it is not known whether the variations of f-TFPI plasma levels are determined by environmental factors. The aim of our study was to evaluate the influence of cardiovascular risk factors on plasma levels of f-TFPI and relations with other endothelial derived molecules in a population of 626 patients (277 men and 349 women) attending a metabolic ward for primary prevention of coronary disease. Free and total TFPI plasma levels were poorly correlated. f-TFPI levels increased with age in both sexes, t-TFPI in women only. Age-adjusted correlations of TFPI levels with conventional cardiovascular risk factors and endothelial cell markers showed different patterns for f-TFPI and t-TFPI. f-TFPI correlated with parameters associated with insulin resistance, particularly in females. f-TFPI was also positively associated in both genders with fibrinogen and endothelial cell markers: t-PA, thrombomodulin (TM) and von Willebrand factor (vWF). t-TFPI correlated strongly with LDL-C in both sexes. It also correlated negatively with parameters of the insulin resistance syndrome. t-TFPI also correlated with TM but not with other endothelial cell markers. The results of the multivariate step by step analysis showed that cardiovascular risk factors poorly explained the f-TFPI variability (7% and 4% in men and women, respectively), whereas they explained 16 and 20% of t-TFPI variability in men and women respectively (mostly related to LDL-C). In conclusion, this study showed that free- and total-TFPI are regulated differently. f-TFPI strongly correlates with endothelial cell markers and t-TFPI is more related to conventional cardiovascular risk factors. The strong gender effect on f-TFPI levels remains to be explained.     

Job strain associated CRP is mediated by leisure time physical activity: Results from the MONICA/KORA study

BackgroundPsychological stress at work is considered a cardiac risk factor, yet whether it acts directly through neuroimmune processes, or indirectly by increasing behavioral risk factors, is uncertain. Cross-sectional associations between job strain and serum biomarkers of inflammation and endothelial dysfunction were investigated. Secondary analyses explored the role of psychosocial/cardiometabolic risk factors as mediators of job stress associated inflammation in healthy workers.MethodsInformation on risk factors was obtained in standardized personal interviews of a subcohort of working participants in the MONICA/KORA population (n = 951). Work stress was measured by the Karasek job strain index. Biomarkers were measured from non-fasting venous blood. Multivariate regression analyses were used to examine the association of job strain with inflammatory biomarkers. Mediation analysis (Sobel test) was used to determine the effect of psychosocial risk factors on the association between job strain and C-reactive protein (CRP).ResultsHigh job strain was reported by half (n = 482, 50.7%) of the study participants. While workers with high job strain were more likely to have adverse workplace conditions (competition with coworkers, job dissatisfaction and insecurity), sleeping problems, depressive symptoms, a Type A personality, and be physically inactive, no differences in cardiometabolic risk factors were detected. A strong and robust association between job strain and CRP was observed in age and sex adjusted models, as well as models adjusted for classic coronary heart disease risk factors (β = 0.39, p = 0.006 and β = 0.27, p = 0.03, respectively). Adjustment for physical activity abrogated this effect (β = 0.23, p = 0.07), and a mediating effect of physical activity on stress-associated inflammation was demonstrated (p = 0.04).ConclusionsThe analyses provide evidence for both a direct and an indirect effect of job strain on inflammation.     

Association of cardiovascular risk factors and disease with depression in later life.

OBJECTIVE: The objective of this study is to determine the association between established cardiovascular risk factors and depression among older men. METHODS: The authors conducted a cross-sectional study of a community-representative sample of 5,439 men aged 71-89 years. Cardiovascular disease and risk factors assessed included history of diabetes, hypertension, angina, myocardial infarction, and stroke; current smoking; total cholesterol and fractions; triglycerides; total plasma homocysteine; and MTHFR677 genotype. Depression was defined by a Geriatric Depression Scale 15 items score of 7 or greater. RESULTS: A complete data set was available for 4,204 men, of whom 212 were depressed (5%). Men who were depressed reported higher frequency of diabetes (23.1% versus 13.2%), angina (30.2% versus 20.4%), myocardial infarction (26.2% versus 16.0%), and stroke (23.6% versus 9.1%) than nondepressed men. Participants with depression were also more likely to have plasma homocysteine above 15 mumol/L (39.1% versus 25.5%) and high triglycerides (32.1% versus 20.9%) than nondepressed subjects. Depressed older men were also more likely to be active smokers (9.9% versus 4.8%). The other factors measured in the study were not significantly associated with depression. Estimation of the population-attributable fraction (PAF) after logistic regression showed that high plasma homocysteine had the highest PAF for depression (PAF:15%, 95% confidence interval [95% CI]: 5%-23%) followed by high triglycerides (PAF: 11%, 95% CI: 2%-18%), angina (PAF: 9%, 95% CI: 2%-15%), stroke (PAF: 8%, 95% CI: 3%-13%), diabetes (PAF: 7%, 95% CI: 1%-13%), myocardial infarction (PAF: 5%, 95% CI: 0%-11%), and smoking (PAF: 5%, 95% CI: 1%-9%). CONCLUSIONS: High plasma homocysteine and triglycerides appear to account for a considerable proportion of cases of depression in older men. The successful management of these risk factors may contribute to decrease the prevalence of depression in later life.     

Carotid plaque, intima media thickness, cardiovascular risk factors, and prevalent cardiovascular disease in men and women: the British Regional Heart Study

BACKGROUND AND PURPOSE: B-mode ultrasound is a noninvasive method of examining the walls of peripheral arteries and provides measures of the intima-media thickness (IMT) at various sites (common carotid artery, bifurcation, internal carotid artery) and of plaques that may indicate early presymptomatic disease. The reported associations between cardiovascular risk factors, clinical disease, IMT, and plaques are inconsistent. We sought to clarify these relationships in a large, representative sample of men and women living in 2 British towns. METHODS: The study was performed during 1996 in 2 towns (Dewsbury and Maidstone) of the British Regional Heart Study that have an approximately 2-fold difference in coronary heart disease risk. The male participants were drawn from the British Regional Heart Study and were recruited in 1978-1980 and form part of a national cohort study of 7735 men. A random sample of women of similar age to the men (55 to 77 years) was also selected from the age-sex register of the general practices used in the original survey. A wide range of data on social, lifestyle, and physiological factors, cardiovascular disease symptoms, and diagnoses was collected. Measures of right and left common carotid IMT (IMTcca) and bifurcation IMT (IMTbif) were made, and the arteries were examined for plaques 1.5 cm above and below the flow divider. RESULTS: Totals of 425 men and 375 women were surveyed (mean age, 66 years; range, 56 to 77 years). The mean (SD) IMTcca observed were 0. 84 (0.21) and 0.75 (0.16) mm for men and women, respectively. The mean (SD) IMTbif were 1.69 (0.61) and 1.50 (0.77) mm for men and women, respectively. The correlation between IMTcca and IMTbif was similar in men (r=0.36) and women (r=0.38). There were no differences in mean IMTcca or IMTbif between the 2 towns. Carotid plaques were very common, affecting 57% (n=239) of men and 58% (n=211) of women. Severe carotid plaques with flow disturbance were rare, affecting 9 men (2%) and 6 women (1.6%). Plaques increased in prevalence with age, affecting 49% men and 39% of women aged <60 years and 65% and 75% of men and women, respectively, aged >70 years. Plaques were most common among men in Dewsbury (79% affected) and least common among men in Maidstone (34% affected). IMTcca showed a different pattern of association with cardiovascular risk factors from IMTbif and was associated with age, SBP, and FEV1 but not with social, lifestyle, or other physiological risk factors. IMTbif and carotid plaques were associated with smoking, manual social class, and plasma fibrinogen. IMTbif and carotid plaques were associated with symptoms and diagnoses of cardiovascular diseases. IMTbif associations with cardiovascular risk factors and prevalent cardiovascular disease appeared to be explained by the presence of plaques in regression models and in analyses stratified by plaque status. CONCLUSIONS: IMTcca, IMTbif, and plaque are correlated with each other but show differing patterns of association with risk factors and prevalent disease. IMTcca is strongly associated with risk factors for stroke and with prevalent stroke, whereas IMTbif and plaque are more directly associated with ischemic heart disease risk factors and prevalent ischemic heart disease. Our analyses suggest that presence of plaque, rather than the thickness of IMTbif, appears to be the major criterion of high risk of disease, but confirmation of these findings in other populations and in prospective studies is required. The association of fibrinogen with plaque appears to be similar to its association with incident cardiovascular disease. Further work elucidating the composition of plaques using ultrasound imaging would be helpful, and more data, analyzed to distinguish plaque from IMTbif and IMTcca, are required to understand the significance of thicker IMT in the absence of plaque.     

Loneliness and neuroendocrine, cardiovascular, and inflammatory stress responses in middle-aged men and women

Loneliness is a psychological experience related to social isolation and perceived lack of companionship, and may be relevant to health risk. The revised UCLA loneliness scale was completed by 240 working men and women aged 47-59 years, and related to affective state and neuroendocrine, cardiovascular, and inflammatory responses. Loneliness scores were not associated with gender, age or socioeconomic position, but were lower in married than single or divorced participants, and were positively related to social isolation, low emotional support, ratings of depression, hopelessness and low self-esteem, and to reported sleep problems. Diastolic blood pressure reactions to acute mental stress were positively correlated with loneliness in women but not men, independently of age, socioeconomic status, smoking, body mass and marital status (p = 0.014). Lonely individuals also displayed significantly greater fibrinogen (p = 0.038) and natural killer cell responses (p = 0.042) to stress, independently of covariates. The cortisol response over the first 30 min following waking was positively associated with loneliness after adjusting for waking cortisol value, sex, socioeconomic status, smoking, time of waking, and body mass (p = 0.046). We conclude that loneliness is a psychological experience with potentially adverse effects on biological stress processes that may be relevant to health.     

Association between actigraphy-based sleep duration variability and cardiovascular risk factors – Results of a population-based study

BackgroundAlthough a few studies suggest an adverse effect of sleep duration variability on cardiovascular risk factor, others did not and this association remains controversial. Moreover, most studies were non-representative of the general population, used different sleep duration variability measures, and relied on self-reported sleep duration. We aimed to assess the association between different, actigraphy-based sleep duration variability measures and cardiovascular risk factors in a population-based sample.MethodsIn a middle-aged population-based cohort, 2598 subjects had data on sleep duration variability measured by actigraph over 14 days. Multivariable logistic regressions were performed to assess the relationship between different sleep duration variability measures [ie, night-to-night variability (NNV), range between shortest and longest sleep duration (RSL), range between average weekday and weekend sleep duration (RWW)] and cardiovascular risk factors including obesity, diabetes and hypertension.ResultsSubjects with highest sleep duration variability - measured as NNV, RSL and RWW, were more likely to be obese. These associations robust in most but not all sensitivity analyses, and no associations between sleep duration variability measures and diabetes or hypertension were found.ConclusionThere is a possible association between high sleep duration variability and obesity, although results were not robust in all sensitivity analyses. Further, no associations between sleep duration variability and other cardiovascular risk factor such as diabetes or hypertension were found.     

Serum inflammatory proteins and frontal lobe dysfunction in patients with cardiovascular risk factors

Background: Recent studies have shown that the levels of circulating inflammatory markers are associated with cognitive decline and cerebral small‐vessel disease. Frontal lobe dysfunction is believed to be a relatively characteristic neuropsychological symptom in vascular cognitive impairment caused by cerebral small‐vessel disease. The purpose of this study was to investigate whether the levels of serum inflammatory markers are associated with frontal lobe dysfunction, particularly executive dysfunction. Methods: Between January 2003 and September 2007, 388 patients who had one or more atherosclerotic risk factors and subsequently underwent brain MRI and neuropsychological testing including mini‐mental state examination (MMSE), frontal assessment battery (FAB), and modified Stroop test were enrolled in this study. We evaluated the effect of serum levels of inflammatory markers and white matter lesions on frontal lobe function. Results: The FAB score was negatively correlated with serum inflammatory marker levels (hsCRP; r = ?0.170, IL‐6; r = ?0.143, IL‐18; r = ?0.175) and white matter lesions. In the modified Stroop test, interference measure was positively correlated with the levels of hsCRP (r = ?0.198), and IL‐18 (r = ?0.152), and white matter lesions. However, the MMSE score was not correlated with either inflammatory marker levels. The association between hsCRP and FAB score or interference measure remained significant when controlling for other confounding factors and MRI findings. Conclusions: The circulating level of hsCRP is associated with frontal lobe dysfunction in patients with cardiovascular risk factors independent of white matter lesions in brain MRI.     

Alexithymia and risk of death in middle-aged men

We prospectively examined the association between alexithymia and risk of death over an average follow-up time of nearly 5.5 years in 42- to 60-year-old men (N = 2297) participating in the Kuopio Ischemic Heart Disease Risk Factor Study (KIHD). Alexithymia, impairment in identification, processing, and verbal expression of inner feelings, was assessed by the validated Toronto Alexithymia Scale (TAS) In age-adjusted survival analyses, men in the highest alexithymia quintile had a twofold greater risk of all-cause death (p<0.001) and a threefold greater risk of death from accidents, injury, or violence (p<0.02) relative to the men in the three lowest alexithymia quintiles. There was little evidence for confounding by behavioral factors (smoking, alcohol consumption, physical activity), physiological risk factors (LDL, HDL, body mass index, hypertension), socioeconomic status, marital status, perceived health, prior diseases and diagnoses, depressive symptoms or social connections. Consistent and even stronger associations between alexithymia and all-cause death were found in a healthy subgroup (N = 1650). Why difficulties in dealing with emotions associate with increased mortality remains unclear. Our findings suggest that the association is independent from the effect of well-known behavioral, biological, and psychosocial risk factors.     

Socioeconomic status variables predict cardiovascular disease risk factors and prospective mortality risk among women with chest pain. The WISE Study

This study examined the relationship between socioeconomic status (SES), coronary artery disease (CAD) risk factors, and all-cause mortality in a cohort of women with chest pain. A total of 743 women (mean age = 59.6 years) with chest pain who were referred for coronary angiography completed a diagnostic protocol including CAD risk factor assessment, ischemic testing, psychosocial testing, and queries of SES. Patients were followed for about 2 years to track subsequent all-cause mortality. Results indicated that low SES was associated with CAD risk factors, including higher BMI and waist-hip ratios, cigarette smoking, lower reported activity levels, and a greater probability of hypertension. Low income also predicted all-cause mortality (RR = 2.7, 95% CI 1.4, 5.2), including after adjusting for proposed psychosocial and behavioral variables (RR = 5.9, 95% CI 1.2-29.7). Future research will require a thorough a priori focus on potential mechanisms to better understand SES effects on health.     

Vital exhaustion increases the risk of ischemic stroke in women but not in men: Results from the Copenhagen City Heart Study

Background

Several studies have indicated an association between depression and the development of stroke, but few studies have focused on gender differences, although both depression and stroke are more common in women than in men. The aim of the present study was to describe whether vital exhaustion, a measure of fatigue and depression, prospectively predicts ischemic and hemorrhagic strokes in a large cohort, with particular focus on gender differences.

Methods

The cohort was composed of 5219 women and 3967 men without cardiovascular disease who were examined in the Copenhagen City Heart Study in 1991-1994. Subjects were followed for 6-9 years. Fatal and nonfatal strokes were ascertained from the Danish National Register of Patients. Cox proportional hazards model was used to describe vital exhaustion as a potential risk factor for stroke.

Results

Four hundred nine validated strokes occurred. A dose-response relationship between vital exhaustion score and the risk of stroke was found in women reaching a hazard ratio (HR) of 2.27 (95% confidence interval: 1.42-3.62) for the group with the highest score. HR was only slightly attenuated by multivariate adjustment. There was no association between vital exhaustion score and stroke in men. HR was strongest for ischemic stroke, whereas no association was seen for hemorrhagic stroke.

Conclusion

Vital exhaustion, a measure of fatigue, conveyed an increased risk of ischemic stroke in women, but not in men, in this study sample.     

Vegetarians and cardiovascular risk factors: hemostasis, inflammatory markers and plasma homocysteine.

We studied hemostatic and inflammatory cardiovascular risk factors (CVRF), and total plasma homocysteine (tHcy) in 26 vegetarians (23 lacto- or ovolactovegetarians and 3 vegans), matched by age, sex and socioeconomic status with omnivorous controls. Vegetarians had significantly lower proportion of eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids in plasma lipids, significantly shortened bleeding time, and increased blood platelet count and in vitro platelet function (aggregation and secretion). Plasma levels of all coagulation or fibrinolytic factors and natural inhibitors synthesized in the liver were lower in vegetarians than in controls. Whereas for some factors this decrease was statistically significant (fibrinogen, factor VIIc, antithrombin III, protein S, plasminogen) for the remaining (factors VIIIc, Vc, prothrombin, protein C) a trend in the same direction was found. For hemostatic proteins of predominantly extrahepatic origin (von Willebrand factor. tPA, PAI-1) this tendency was not present. No significant differences in inflammatory proteins (C-reactive protein and alpha1-protease inhibitor) were detected in both groups. tHcy was significantly increased in vegetarians, and correlated only with cobalamin levels. The increased platelet function and tHcy found in vegetarians may counteract the known cardiovascular health benefits of vegetarian diet (VD).