Andrew J. Wawrzyniak

Synergistic effects of psychological and immune stressors on inflammatory cytokine and sickness responses in humans

Activation of the innate immune system is commonly accompanied by a set of behavioural, psychological and physiological changes known as ‘sickness behaviour’. In animals, infection-related sickness symptoms are significantly increased by exposure to psychosocial stress, suggesting that psychological and immune stressors may operate through similar pathways to induce sickness. We used a double-blind, randomised, placebo-controlled design to examine the effect of acute psychological stress on immune and subjective mood responses to typhoid vaccination in 59 men. Volunteers were assigned to one of four experimental conditions in which they were either injected with typhoid vaccine or saline placebo, and then either rested or completed two challenging behavioural tasks. Typhoid vaccine induced a significant rise in participants’ serum levels of interleukin-6 (IL-6) and this response was significantly larger in the stress versus rest conditions. Negative mood increased immediately post-tasks, an effect also more pronounced in the vaccine/stress condition. In the vaccine/stress group, participants with larger IL-6 responses had heightened systolic blood pressure responses to tasks and elevated post-stress salivary levels of the noradrenaline metabolite 3-methoxy-phenyl glycol (MHPG) and cortisol. Our findings suggest that, as seen in animals, psychological and immune stressors may act synergistically to promote inflammation and sickness behaviour in humans.

Dispositional optimism and stress-induced changes in immunity and negative mood

Evidence suggests that optimism may be protective for health during times of heightened stress, yet the mechanisms involved remain unclear. In a double-blind placebo-controlled study, we recently showed that acute psychological stress and an immune stimulus (Typhim-Vi typhoid vaccine) synergistically increased serum levels of interleukin-6 (IL-6) and negative mood in 59 healthy men. Here we carried out further analysis of this sample to investigate the relationship between dispositional optimism and stress-induced changes in immunity and mood. Volunteers were randomly assigned to one of four experimental conditions in which they received either typhoid vaccine or saline placebo, and then rested or completed two mental tasks. In the stress condition, optimism was inversely related to IL-6 responses, independent of age, BMI, trait CES-D depression and baseline IL-6. This relationship was present across both stress groups (combining vaccine and placebo) and was not present in the vaccine/stress group alone, suggesting that optimism protects against the inflammatory effects of stress rather than vaccine per se. Typhoid vaccine induced a significant increase in participants’ circulating anti-Vi antibody levels. Stress had no effect on antibody responses overall. However, in the vaccine/stress group, there was a strong positive association between optimism and antibody responses, indicating that stress accentuated the antibody response to vaccine in optimists. Across the complete sample, more optimistic individuals had smaller increases in negative mood and less reduction in mental vigour. Together these findings suggest that optimism may promote health, by counteracting stress-induced increases in inflammation and boosting the adjuvant effects of acute stress.

Positive emotional style and subjective, cardiovascular and cortisol responses to acute laboratory stress

The relationships between positive emotional style and acute salivary cortisol and cardiovascular responses to laboratory stress tasks were examined in 40 young women (mean age=28.8 years). Positive emotional style (PES) was measured by aggregating daily positive mood rating scales over one week. Negative affect was assessed with the short form Profile of Mood States. Salivary cortisol was measured in response to two behavioural tasks, a 5 min speech task and a 5 min mirror tracing task. Blood pressure (BP) and heart rate responses were monitored using a Finometer during baseline, tasks and recovery. Higher PES was associated with more complete diastolic BP recovery (p=0.027) and lower acute cortisol response to stress (p=0.018), after adjusting for baseline measures, age, BMI and negative affect. Individuals with higher PES reported lower subjective tension during the tasks and perceived the tasks as more controllable. There were no differences in ratings of task involvement or in objective measures of task performance. A retrospective measure of positive affect (POMS vigour) was associated with diastolic BP recovery but not cortisol responses or subjective tension. The findings suggest that positive affective traits, assessed using repeated assessments of daily mood, are related to adaptive recovery from acute psychological stress. Our results reinforce evidence linking positive affect with adaptive diastolic BP recovery, while extending the results to cortisol. Investigations into the biological correlates of affective traits should consider utilising repeated measures of experienced affect.

Health literacy: impact on the health of HIV-infected individuals.

Health literacy is known to affect vulnerable communities such as persons living with HIV/AIDS. The purpose of this review was to provide a current summary of research on the impact of health literacy on the health of persons living with HIV/AIDS and to address future areas of need. Contemporary studies focused on expanding the reach of health literacy in HIV/AIDS to retention in HIV care, use of technology for assessing and intervening to improve health literacy, and health literacy across the globe, for example. A number of studies did not find health literacy to explain health behaviors whereas other studies supported such a relationship. Future issues relevant to health literacy in HIV/AIDS include the aging of the HIV population and associated comorbidities, studies to understand the role of health literacy in specific populations affected by HIV/AIDS, and the continued need to refine the definition and measurement of health literacy.

Associations of objectively measured physical activity with daily mood ratings and psychophysiological stress responses in women

The aim of this study was to examine associations of objectively measured physical activity with daily mood ratings and psychophysiological stress responses. We recruited 40 healthy females (aged 28.7 ± 6.1 yrs) who completed a once-a-day mood rating scale for 7 days, along with a 7-day assessment of physical activity using accelerometers and psychophysiological stress testing. The findings suggest that levels of physical activity as measured using an accelerometer are associated with both depressive symptoms over the past 2 weeks (CES-D) (r = - .33, p = .038) and with daily positive emotional style (r = .49, p = .001). The relationship between physical activity and positive emotional style remained after controlling for age, body mass index, and negative emotional style (t = 3.31, p = .002). Physical activity was not related to any psychophysiological stress responses.

Circulating Leptin and Stress-induced Cardiovascular Activity in Humans

Obesity is associated with an elevated risk of hypertension and cardiovascular disease. The adipocyte hormone leptin, which stimulates energy expenditure in animals by activating the sympathetic nervous system (SNS), is believed to play a role in this association. However, evidence in humans remains sparse. We investigated the relationship between circulating leptin and cardiovascular and inflammatory responses to acute psychological stress in humans. Participants were 32 men and 62 women aged 18–25 years. Cardiovascular activity was assessed using impedance cardiography at baseline, during acute laboratory stress, and during a 45‐min recovery period. Plasma cytokines were measured in blood drawn at baseline and 45‐min poststress. In women only, baseline plasma leptin was significantly associated with stress‐induced changes in heart rate (β = 0.53, P = 0.006), heart rate variability (HRV) (β = −0.44, P = 0.015), and cardiac preejection period (PEP) (β = −0.51, P = 0.004), independent of age, adiposity, and smoking. Womens plasma leptin levels also correlated with stress‐induced elevations in the proinflammatory cytokine interleukin‐6 (IL‐6) (β = 0.35, P = 0.042). Circulating leptin is an independent predictor of sympathetic cardiovascular activity, parasympathetic withdrawal, and inflammatory responses to stress in women. Because cardiovascular and inflammatory stress responses are predictive of future cardiovascular disease, leptin may be a mechanism mediating the adverse effects of stress and obesity on womens cardiovascular health.

The effects of exercise withdrawal on mood and inflammatory cytokine responses in humans

Mechanisms underlying the relationship between exercise and mood are not well understood. This study sought to investigate the role of pro- and anti-inflammatory cytokines and autonomic balance in determining the impact of exercise withdrawal on negative mood. Healthy men and women who regularly exercised (N = 26, mean age = 25.5 years, SD = 4.5 years) were randomised to exercise withdrawal or exercise maintenance for 2 weeks. Protocol adherence was monitored using accelerometers. Inflammatory markers from plasma (interleukin-6, IL-6; tumour necrosis factor-alpha; interleukin-10; and interleukin-1 receptor antagonist), heart-rate variability (HRV) and measures of mood (General Health Questionnaire-28 (GHQ) and the Profile of Mood States (POMS)) were assessed at study entry and at 2-week follow-up. Exercise withdrawal resulted in significant increases in negative mood over time on both the GHQ (p = 0.028) and the POMS (p = 0.005). Following the intervention, IL-6 concentration was lower in the exercise withdrawal than exercise maintenance condition (p = 0.05). No intervention effects were observed for other cytokines or HRV. The mood changes were significantly related to changes in IL-6 concentration (β = − 0.50, p = 0.011), indicating that reduction in IL-6 was related to increased negative mood. Our results are consistent with positive effects of exercise on mental health, but further research on inflammatory pathways is warranted.

Combining psychosocial data to improve prediction of cardiovascular disease risk factors and events: The National Heart, Lung, and Blood Institute--sponsored Women's Ischemia Syndrome Evaluation study.

Background There is overlap among psychosocial predictors of cardiovascular disease (CVD). The usefulness of combining psychosocial variables as risk markers for CVD needs investigation. Methods Participants were 493 women in the NHLBI WISE study. Multivariate combination of Beck Depression Inventory (BDI), State-Trait Anxiety Inventory (STAI), Social Network Index (SNI), and Cook-Medley hostility subscales was evaluated, and principal components analysis also conducted. Relationships of composite psychosocial risk markers to CVD events and risk factors were assessed. Results The multivariate block of SNI, Cook-Medley Hostile Affect subscale, STAI, and BDI predicted CVD events (&khgr;2 = 27.8, df = 6, p < .001). Scalewise factor analysis revealed 2 factors: negative affectivity (NA) and hostility (explained variance, 45.6% and 17.1%, respectively). NA was associated with BMI (&bgr; [SE] = 0.18 [0.09], p = .04), hostility with metabolic syndrome (exp(&bgr;) = 0.60 [0.28], p = .04). Both factors were associated with blood pressure (BP): NA with SBP (&bgr; = 2.53 [1.04], p = .02) and DBP (&bgr; = 1.66 [0.60], p = .02); hostility with SBP (&bgr; = 2.72 [1.13], p = .02) and DBP (&bgr; = 1.83 [0.65], p = .005). Neither factor predicted CVD events. Original scales predicted CVD events: lower SNI (HR = 0.74, CI = 0.57–0.96), lower Hostile Affect (HR = 0.80, CI = 0.56–1.03), and higher BDI (HR = 1.33, CI = 1.08–1.74). Conclusions In women with suspected ischemia, multivariate combination of psychosocial risk markers predicts CVD events; derived psychosocial factors were associated with CVD risk factors but not events. Measuring common variance among psychosocial variables may be a useful research strategy. Abbreviations CVD = cardiovascular disease; BMI = body mass index; MI = myocardial infarction; CAD = coronary artery disease; CV = cardiovascular; WISE = The Women’s Ischemia Syndrome Evaluation; PCA = principal components analysis; STAI = State-Trait Anxiety Inventory; BDI = Beck Depression Inventory; NA = negative affectivity; CM = Cook-Medley; NHLBI = The National Heart, Lung, and Blood Institute; IHD = ischemic heart disease; BP = blood pressure; SBP = systolic blood pressure; DBP = diastolic blood pressure; SE = standard error; CI = confidence interval

Prognostic significance of active and modified forms of endothelin 1 in patients with heart failure with reduced ejection fraction

OBJECTIVES Concentrations of endothelin I (ET1) are elevated in CHF patients and, like other biomarkers that reflect hemodynamic status and cardiac pathophysiology, are prognostic. The Singulex assay (Sgx-ET1) measures the active form of ET1, with a short in vivo half-life and the Brahms assay measures C-terminal endothelin-1 (CT-ET1), a modified (degraded) product with longer half-life. We aimed to determine the prognostic importance of active and modified forms of endothelin 1 (Singulex and Brahms assays) in comparison with other commonly measured biomarkers of inflammation, hemodynamic status and cardiac physiology in CHF. DESIGN AND METHODS Plasma biomarkers (Sgx-ET1, CT-ET1, NTproBNP, IL-6, TNFα, cTnI, VEGF, hs-CRP, Galectin-3, ST2) were measured in 134 NYHA class II and III CHF patients with systolic dysfunction. Prognostic importance of biomarkers for hospitalization or death were calculated by both logistic regression and Kaplan-Meier survival analyses. RESULTS CT-ET1 (OR=5.2, 95% CI=1.7-15.7) and Sgx-ET1 (OR=2.9, CI=1.1-7.7) were independent predictors of hospitalization and death and additively predicted events after adjusting for age, sex, and other significant biomarkers. Other biomarkers did not improve the model. Similarly, in Cox regression analysis, only CT-ET1 (HR 3.4, 95% CI=1.4-8.4), VEGF (2.7, 95% CI=1.3-5.4), and Sgx-ET1 (HR 2.6, 95% CI=1.2-5.6) were independently prognostic. CONCLUSIONS Elevated concentrations of endothelin 1 predict mortality and hospitalizations in HF patients. Endothelin 1 was more prognostic than commonly obtained hemodynamic, inflammatory, and fibrotic biomarkers. Two different assays of endothelin 1 independently and synergistically were prognostic, suggesting either complementary information or extreme prognostic importance.

High Concordance Between Mental Stress–Induced and Adenosine-Induced Myocardial Ischemia Assessed Using SPECT in Heart Failure Patients: Hemodynamic and Biomarker Correlates

Mental stress can trigger myocardial ischemia, but the prevalence of mental stress–induced ischemia in congestive heart failure (CHF) patients is unknown. We characterized mental stress–induced and adenosine-induced changes in myocardial perfusion and neurohormonal activation in CHF patients with reduced left-ventricular function using SPECT to precisely quantify segment-level myocardial perfusion. Methods: Thirty-four coronary artery disease patients (mean age ± SD, 62 ± 10 y) with CHF longer than 3 mo and ejection fraction less than 40% underwent both adenosine and mental stress myocardial perfusion SPECT on consecutive days. Mental stress consisted of anger recall (anger-provoking speech) followed by subtraction of serial sevens. The presence and extent of myocardial ischemia was quantified using the conventional 17-segment model. Results: Sixty-eight percent of patients had 1 ischemic segment or more during mental stress and 81% during adenosine. On segment-by-segment analysis, perfusion with mental stress and adenosine were highly correlated. No significant differences were found between any 2 time points for B-type natriuretic peptide, tumor necrosis factor-α, IL-1b, troponin, vascular endothelin growth factor, IL-17a, matrix metallopeptidase-9, or C-reactive protein. However, endothelin-1 and IL-6 increased, and IL-10 decreased, between the stressor and 30 min after stress. Left-ventricular end diastolic dimension was 179 ± 65 mL at rest and increased to 217 ± 71 after mental stress and 229 ± 86 after adenosine (P < 0.01 for both). Resting end systolic volume was 129 ± 60 mL at rest and increased to 158 ± 66 after mental stress (P < 0.05) and 171 ± 87 after adenosine (P < 0.07), with no significant differences between adenosine and mental stress. Ejection fraction was 30 ± 12 at baseline, 29 ± 11 with mental stress, and 28 ± 10 with adenosine (P = not significant). Conclusion: There was high concordance between ischemic perfusion defects induced by adenosine and mental stress, suggesting that mental stress is equivalent to pharmacologic stress in eliciting clinically significant myocardial perfusion defects in CHF patients. Cardiac dilatation suggests clinically important changes with both conditions. Psychosocial stressors during daily life may contribute to the ischemic burden of CHF patients with coronary artery disease.