Abstract
Objective
Given the importance of positive affect and inflammation for well-being in cancer survivors, the current study examined the relationship between high and low arousal positive affect and inflammation in 186 women who completed treatment for early-stage breast cancer.
Methods
Measures of high and low arousal positive affect were completed within three months after treatment completion (baseline). Plasma markers of inflammation, including sTNF-RII, CRP, and IL-1ra, were assessed at baseline and 6 and 12 month follow-up assessments.
Results
Multilevel modeling analyses showed that high arousal positive affect was associated with lower levels of sTNF-RII, a marker of TNF activity, at treatment completion and prospectively predicted maintenance of these differences through the 6 and 12 month follow-ups controlling for biobehavioral confounds (b = −.055, t(156) = −2.40, p = .018). However, this association was no longer significant when controlling for fatigue. Exploratory analyses showed that low arousal positive affect was associated with lower levels of CRP at treatment completion and through the 6 and 12 month follow-ups; this association remained significant controlling for fatigue and other confounds (b = −.217, t(152) = −2.04, p = .043).
Conclusion
The relationship of high arousal positive affect (e.g., “active”) with sTNF-RII appears to be driven by the overlap of high arousal positive affect with fatigue while the relationship of low arousal positive affect (e.g., “calm”) with CRP was independent of fatigue. Future research should consider affective arousal when examining the association of positive affect with inflammation as this facet of positive affect may have important implications for interpretation of results.
Keywords: positive affect, breast cancer, inflammation, arousal
Although research has traditionally focused on the deleterious effects of chronic stress and its correlates (1), more recent investigations have produced evidence for the influence of positive psychological processes on health. In particular, positive affect, defined as the presence of emotional states that are positive in valence, has been linked to lower overall morbidity and mortality (2, 3). However, despite the association of positive affect with improved health outcomes, the physiological mechanisms that underlie this association have not been determined. In addition, there has been minimal examination of positive affect and physiological processes in clinical populations, despite relevance for health and well-being. Thus, the aim of the current study was to examine the prospective association of high and low arousal positive affect with markers of inflammation in a sample of women with early stage breast cancer who recently completed primary cancer treatment.
Positive affect has been prospectively associated with improved outcomes for a wide variety of diseases (e.g., 3–7). In the cancer context, preliminary studies have found that positive affect is associated with lower cancer-related mortality among breast cancer patients with recurrent disease (8) and patients with metastatic renal cell carcinoma (9). Women with early stage, non-recurrent breast cancer have high survival rates but are at risk for other health comorbidities that have been linked with positive affect, including cardiovascular disease (10). Further, positive affect is associated with improved psychological adjustment in cancer survivors, including lower anxiety, depressive symptoms, pain, and fatigue, as well as greater quality of life (11–13). Evidence suggests that levels of positive affect reported by cancer survivors are generally high and comparable to healthy adult samples (13,14).
Despite evidence for the association between positive affect and improved health outcomes, there has been limited research examining the intermediate mechanisms that may account for the salutary effects of positive affect. One plausible mechanism may be inflammation given its association with all-cause mortality (15) and the onset and progression of a variety of diseases (including many that have been linked to positive affect; e.g., 16, 17). Research by Steptoe and colleagues (18) aggregating daily assessments of positive affect in healthy middle-aged adults found an inverse relationship between positive affect and circulating levels of interleukin-6 (IL-6) and CRP. In addition, these investigators found that positive affect predicted lower reactivity and more efficient recovery of fibrinogen in response to a mental stress task in both men and women (19). Nevertheless, other studies examining positive affect and inflammatory markers have produced mixed results (20–22).
Given our interest in the association of positive affect and physiology, an important defining dimension of positive affect to consider is its level of arousal. The Circumplex Model of Affect (23) characterizes affect on two dimensions: valence and arousal. Valence ranges from positive to negative, while arousal ranges from high to low activation. Differentiating between high arousal positive affect (e.g., excitement) and low arousal positive affect (e.g., contentment) may be of particular importance as affective arousal has consequences for physiological arousal (24, 25). Specifically, autonomic activation is particularly sensitive to high versus low arousal positive affect in mood induction studies with evidence suggesting that high arousal positive affect is associated with greater autonomic activation than low arousal positive affect (for review see reference 25). This may in turn have implications for inflammatory processes, given autonomic regulation of the immune system (26). Nevertheless, research investigating differences in the association of high versus low arousal positive affect with inflammatory processes is lacking.
Studies have investigated the effects of high versus low arousal positive affect on other immune and physiological processes. High arousal positive affect (but not low arousal positive affect) has been shown to predict the development of fewer colds following exposure to a rhinovirus or influenza A virus (4,27), steeper cortisol slopes from waking to bedtime and lower evening cortisol (28), and increased longevity (29). Yet, other observational studies have not found differential effects of high versus low arousal positive affect on immune processes, including antibody responses to the hepatitis B vaccine (30) or immune responses (e.g., natural killer cell percentage and activity and percentage of suppressor/cytotoxic T cells) to an experimental mood induction (31). Of note, self-report measures of high and low arousal positive affect vary across observational studies. Although most studies use some combination of the descriptors “calm,” “relaxed,” and “at ease” for the assessment of low arousal positive affect (4,27–30), the measurement of high arousal positive affect is more variable. Previous studies have included all or select items (e.g., “active,” “alert”) from the commonly-used PANAS (32) positive affect subscale (28,29), while others have used other descriptors (e.g., “lively,” “full-of-pep,” “energetic”; 4,27,30). The current study builds on this emerging literature and uses previous research to inform its assessment of high and low arousal positive affect.
Examining predictors of inflammation in breast cancer survivors is of particular interest given that inflammation has been associated with recurrence and survival among women treated for early-stage breast cancer (33,34). In addition, inflammation has been associated with behavioral symptoms that plague many breast cancer survivors, including fatigue and depression (e.g., 35–37), and is also associated with other health comorbidities that are elevated in this population (38). In order to advance our understanding of positive affect and inflammation in the cancer context, the aim of the present study was to longitudinally examine the prospective relationship of high and low arousal positive affect with circulating markers of inflammation among women with early-stage breast cancer who were followed for a year after treatment with surgery, radiation, and/or chemotherapy. Given evidence supporting the association of positive affect and improved health and well-being, we hypothesized that both high and low arousal positive affect would predict lower levels of inflammatory markers at post-treatment and at 6 month and 12 month follow-up assessments controlling for potential biobehavioral confounds. In particular, we were interested in examining the unique association of positive affect and inflammation controlling for negative affect and fatigue given the previous research supporting the association of these factors with inflammation in the cancer context.
Method
Participants
Study participants were recruited to participate in a prospective observational cohort study of cognitive functioning after treatment for breast cancer conducted at the University of California, Los Angeles (UCLA). A detailed description of recruitment and assessment procedures for the primary study can be found elsewhere (39). To be eligible, women were required to be between 21 to 65 years of age with a diagnosis of stage 0 to IIIA breast cancer, prior to beginning endocrine therapy and within three months of completing primary cancer treatment (i.e., surgery, radiation therapy, and/or chemotherapy). Of the 191 women originally enrolled to participate, questionnaire data was unavailable for 5 participants, thus our primary analyses focus on women who completed the baseline psychological measures of interest (n = 186).
Procedures
Study participants were identified primarily through tumor registry rapid case ascertainment from hospitals where collaborating physicians practiced as well as through direct referral from surgical and medical oncology practices. Recruitment began in May 2007 and ended in February 2011. Women received a brochure describing the study and were asked to contact the research office if they were interested in participating. A phone screen was conducted to determine eligibility and women who were eligible were subsequently scheduled for an in-person appointment at UCLA during which they provided blood samples via venipuncture and completed self-report questionnaires and neuropsychological assessments. Weight and height measurements were also obtained in order to determine body mass index (BMI). In addition, women completed comprehensive neuropsychological assessments as part of the parent study.
Participants returned to the laboratory 6 and 12 months after the baseline in order to complete follow-up assessments during which they provided blood samples and completed questionnaires and neuropsychological assessments. All assessments were conducted in the morning before 11:00 AM. These assessments were structured to examine the impact of adjuvant endocrine therapies on cognitive functioning following primary treatment for breast cancer (39–41); however they presented us with the unique opportunity to examine the relationship of positive affect with inflammation in the year after breast cancer treatment. This research was approved the University of California, Los Angeles institutional review board. Informed consent was obtained from all participants.
Measures
Demographic information, including age, ethnicity, relationship status, and socioeconomic status, was collected at baseline by self-report questionnaire. Cancer and treatment-related information (i.e., stage, time since treatment completion and treatment with chemotherapy, radiation therapy, and/or endocrine therapy) was determined from medical chart reviews. Menopausal status was self-reported at baseline.
Questionnaires
High arousal positive affect at baseline was assessed using the four high arousal items from the positive affect subscale of the Positive and Negative Affect Scale (PANAS; 32): “excited,” “active,” “alert,” and “enthusiastic.” This is consistent with previous research that has used all or select items of this subscale to assess high arousal positive affect (28,29). This measure assesses the extent to which a participant has experienced each high arousal positive affect item during the past month on a scale of 1 = “very slightly or not at all” to 5 = “extremely.” Items are averaged. Internal consistency was adequate in this sample (α = .854).
Low arousal positive affect at baseline was assessed using two low arousal positive affect items from the Serenity subscale of the PANAS-X (an expansion of the original PANAS questionnaire; 42):“calm” and “relaxed.” The third item (“at ease”) was not included in our questionnaire. This is consistent with previous research that has used these two items to asses low arousal positive affect (4,27–30). This measure assesses the extent to which a participant has experienced each low arousal positive affect item during the past week on a scale of 1 = “very slightly or not at all” to 5 = “extremely.” Items are averaged. The inter-item correlation for this measure was high (r = .78, p < .001).
To determine whether any associations between high and low arousal positive affect and inflammatory markers are driven by negative affect (or lack thereof), we assessed negative affect at baseline using the negative affect subscale of the Positive and Negative Affect Scale (PANAS; 32). This measure assesses the extent to which a participant has experienced negative affect during the past month on the same 1-5 scale. Items of the negative affect scale are: “afraid,” “scared,” “nervous,” “jittery,” “irritable,” “hostile,” “guilty,” “ashamed,” “upset,” and “distressed.” Furthermore, given the potential overlap of positive affect, particularly high arousal positive affect, and fatigue, and evidence that fatigue is linked to inflammation in breast cancer survivors (including a subset of patients in this sample; 35), fatigue was also examined as a potential confounder in analyses. Fatigue severity was assessed at baseline using Fatigue Symptom Inventory (43), which includes items assessing “most”, “least”, and “average” fatigue in the past week on a 0-10 scale.
Inflammatory markers
Blood samples at baseline as well as at 6 and 12 month follow-up assessments were collected by venipuncture into EDTA tubes, placed on ice, centrifuged for acquisition of plasma, and stored at −80°C for subsequent batch testing. We focused on downstream markers of proinflammatory cytokine activity, which are typically produced in larger quantities than the cytokines that induce their production and may provide a more reliable and stable index of cytokine activity (44, 45). These included the interleukin-1 receptor antagonist (IL-1ra), a marker of IL-1β activity; the soluble tumor necrosis factor (TNF) receptor type II (sTNF-RII), a marker of TNF-α activity; and C-reactive protein (CRP), a correlate of IL-6 activity. Plasma levels of IL-1ra and sTNF-RII were determined by enzyme-linked immunosorbent assay (R&D Systems, Minneapolis, MN) according to the manufacturer’s protocols with a lower limit of detection of 31 and 234 pg/mL for IL-1ra and sTNF-RII, respectively. CRP levels were determined by a high-sensitivity enzyme-linked immunosorbent assay (Immundiagnostik; ALPCO Immunoassays, Salem, NH) according to the manufacturer’s protocol but with an extended standard curve to a lower limit of detection of 0.2 mg/L. All samples were run in duplicate, and assays were repeated on two separate assay days for sTNF-RII and IL-1ra; intra-assay and inter-assay mean levels were used in all analyses. The intra- and interassay precision of all tests were less than or equal to 10%. Immune data for women with a diagnosis of neurologic or immune-related medical conditions (e.g., autoimmune diseases) or an acute infection were excluded (n = 4).
Statistical Analyses
Descriptive analyses were conducted with SPSS version 18.0. In order to examine the relationship of positive affect with inflammation over time, a two-level multilevel model with time points nested within individuals was run to test the associations of high and low arousal positive affect at baseline with markers of inflammation over the one-year assessment period using SAS version 9.3. Although assessed at all three time points, we focus our analyses on the baseline assessment of high and low arousal positive affect given our interest in prospectively predicting inflammation by levels of positive affect and the fact that repeated measures analysis of variance (ANOVA) analyses revealed no change over time for both positive affect measures (p’s > .05). Multilevel models are well suited for longitudinal data as they account for the non-independence of repeated observations. We focus our interpretation on the fixed effects of the model.
Analyses controlled for key covariates that are known to influence inflammation, including age, BMI, and menopausal status (46). We also controlled for cancer-specific covariates, including stage of disease, cancer treatment (radiation, chemotherapy, endocrine therapy), and time since last treatment. Note that all women had completed radiation and/or chemotherapy before their baseline assessment, while endocrine therapy could be ongoing throughout the follow-up. Thus, main effects for radiation and chemotherapy were included at the baseline assessment, whereas endocrine therapy was included as a time-varying covariate. Preliminary analyses indicated that chemotherapy also influenced the changes in inflammatory markers over the follow-up; to account for this effect, a time by chemotherapy interaction was included in the final model. The following covariates were grand-mean centered to aid interpretation: age, months since last treatment, and BMI. Preliminary analyses were also conducted to evaluate whether positive affect influenced the changes in inflammatory markers over time, however these were non-significant, therefore no positive affect by time interaction was included in the model for either high or low arousal positive affect.
Final models included both a random intercept and slope for time at Level 1. The markers of inflammation (i.e., sTNF-RII, IL-1ra, and CRP) were treated as Level 1 outcomes with baseline positive affect as the Level 2 predictor of interest. Age, negative affect, BMI, menopausal status, treatment with chemotherapy and/or radiation therapy, time since treatment completion, cancer stage, and fatigue were all measured at baseline and included as Level 2 covariates. Treatment with endocrine therapy was assessed at each time point and entered as a Level 1 covariate. All values for markers of inflammation were log transformed in order to correct for non-normality. In order to report the effect sizes of high and low arousal positive affect, we employed the approach proposed by Raudenbush and Byrk (47), which estimates the residual variance at each level of the multilevel model in both a restricted model without the effect of interest and in a complete model with the effect of interest included. This allows for comparison of the two variance components to determine how much variance is accounted for by the predictor of interest over and above covariates.
Results
Sample demographics are reported in Table 1. On average, participants were 52 years old (SD = 8.29), White (84%), partnered (77%) women with college or graduate educations (82%) and annual household incomes greater than $100,000 (60%). Women tended to have earlier-stage cancers (13% stage 0, 46% stage I, 32% stage II, and 10% stage III). More women underwent lumpectomies than mastectomies (66% versus 34%), 74% received radiation therapy, 52% received chemotherapy, and 68% of women received endocrine therapy at one or both of the follow up assessments.
Table 1.
Demographic and Medical Characteristics of Sample (n = 186)
| N (%) or Mean (SD) | |
|---|---|
|
| |
| Age (years) | 51.68 (8.29) |
| Race | |
| White | 154 (83.7%) |
| Other | 30 (15.3%) |
| Don’t know/Refuse | 2 (1.0%) |
| Hispanic Ethnicity | |
| Yes | 20 (10.9%) |
| No | 164 (89.1%) |
| Marital Status | |
| Married/Partnered | 143 (76.9%) |
| Not Married/Partnered | 43 (23.1%) |
| Education | |
| Graduate Degree or Training | 97 (52.2%) |
| College Degree | 55 (29.6%) |
| Some college/Associate | 30 (16.1%) |
| Degree | |
| High School/Vocational | 4 (2.1%) |
| Training | |
| Employment | |
| Full or Part-time | 121 (65.1%) |
| Not Employed | 65 (34.9%) |
| Annual Household Income | |
| ≤$60,000 | 23 (12.0%) |
| $60,001-100,000 | 51 (27.9%) |
| >$100,000 | 110 (60.1%) |
| Menopausal Status | |
| Post-menopausal before
cancer |
97 (52.2%) |
| Premenopausal | 49 (26.3%) |
| Treatment-induced | 40 (21.5%) |
| Menopause | |
| Stage | |
| 0 | 24 (12.9%) |
| I | 85 (45.7%) |
| II | 59 (31.7%) |
| III | 18 (9.7%) |
| Type of Surgery | |
| Mastectomy | 64 (34.4%) |
| Lumpectomy | 122 (65.6%) |
| Months since Last Primary
Treatment |
1.18 (1.04) |
| Received Chemotherapy | |
| Yes | 97 (52.2%) |
| No | 89 (47.8%) |
| Received Radiation | |
| Yes | 138 (74.2%) |
| No | 48 (25.8%) |
| Received Endocrine Therapy | |
| Baseline | 0 (0%) |
| 6 month follow up | 127 (68.3%) |
| 12 month follow up | 125 (67.2%) |
| Body Mass Index (kg/m2) | 25.66 (5.35) |
On average, women reported “moderate” high arousal positive affect (M = 3.06, SD = .87) and “a little” to “moderate” low arousal positive affect (M = 2.16, SD = .96). High arousal positive affect was negatively correlated with negative affect (r = −.42, p < .001), BMI (r = −.17, p =.021), and fatigue (r = −.49, p <.001) as well as positively correlated with low arousal positive affect (r = .58, p < .001). Similarly, low arousal positive affect was negatively correlated with negative affect (r = −.55, p < .001) and fatigue (r = −.34, p <.001) and positively correlated with age (r =.19, p = .009). Neither high nor low arousal positive affect were associated with cancer stage, time since primary treatment, or treatment with chemotherapy, radiation therapy, and endocrine therapy. Descriptive statistics for markers of inflammation at baseline, 6 and 12 month follow up assessments are reported in Table 2.
Table 2.
Descriptive Statistics for Markers of Inflammation at Baseline, 6 and 12 month Follow Up Assessments
| Baseline (n = 171) |
6 mo. Follow Up (n = 157) |
12 mo. Follow Up (n = 154) |
||||
|---|---|---|---|---|---|---|
|
| ||||||
| Mean | SD | Mean | SD | Mean | SD | |
| sTNF-RII (pg/ml) | 2329.45 | 675.02 | 2050.85 | 520.54 | 2028.41 | 537.96 |
| IL1-ra (pg/ml) | 289.92 | 294.35 | 252.70 | 196.44 | 253.60 | 161.03 |
| CRP (mg/l) | 2.96 | 5.71 | 1.89 | 3.56 | 2.37 | 5.20 |
Prospective Association of High Arousal Positive Affect with Inflammation
The primary goal of this study was to examine the association between high and low arousal positive affect and levels of inflammatory markers over time. Consistent with hypotheses, results indicate that high arousal positive affect was associated with significantly lower levels of sTNF-RII at the baseline assessment as well as the 6 month and 12 month follow up assessments (b = −.055, t(156) = −2.40, p = .018), controlling for age, BMI, menopausal status, cancer stage, time since last treatment, radiation, endocrine therapy, chemotherapy, the interaction between chemotherapy and the linear trend for time, and negative affect . Thus, individuals with higher levels of high arousal positive affect demonstrated lower levels of sTNF-RII across the three time points, independent of negative affect. This effect accounted for approximately 12% of the residual intercept variance not accounted for by other covariates in the model. However, when fatigue was included in the model, the association of high arousal positive affect was attenuated and became non-significant (Table 3; b = −.030, t(153) = −1.24, p = .218). High arousal positive affect at baseline was not associated with CRP or IL-1ra at baseline or prospectively at 6 and 12 month follow up assessments in models with or without fatigue (p’s > .05). To facilitate comparison with studies using the full positive affect subscale of the PANAS (32), we also performed analyses using the 10-item positive affect subscale, which oversamples high arousal positive affect and excludes low arousal positive affect items (25,29). Results were consistent with those reported above; specifically, the 10-item positive affect subscale was associated with lower levels of sTNF-RII in analyses that did not include fatigue, and this association became non-significant when controlling for fatigue.
Table 3.
High Arousal Positive Affect and Related Covariates as Predictors of sTNF-RII in a Two-Level Multilevel Model using Restricted Maximum Likelihood (REML) Estimation (n = 186)
| sTNF-RII | |||
|---|---|---|---|
|
| |||
| B | SE | P value | |
| Intercept | 7.760 | .133 | <.001 |
| Time | −.006 | .013 | .634 |
| High Arousal Positive Affect | −.030 | .025 | .218 |
| Negative Affect | −.007 | .003 | .022 |
| Age | .008 | .003 | .014 |
| Body Mass Index (BMI) | .006 | .003 | .081 |
| Fatigue Severity | .025 | .010 | .012 |
| Cancer Stage (0 is reference group) | |||
| I | .034 | .061 | .574 |
| II | .057 | .072 | .432 |
| III | .094 | .089 | .292 |
| Menopausal Status | |||
| (Post-menopausal before cancer is reference group) | |||
| Premenopausal | −.039 | .057 | .497 |
| Treatment-induced Menopause | .006 | .061 | .921 |
| Months since Last Treatment | −.032 | .020 | .119 |
| Radiation Therapy | −.019 | .046 | .674 |
| Endocrine Therapy | −.054 | .018 | .003 |
| Chemotherapy | .090 | .056 | .108 |
| Time*Chemotherapy | −.075 | .015 | <.001 |
Prospective Association of Low Arousal Positive Affect with Inflammation
Low arousal positive affect was associated with significantly lower levels of CRP at the baseline assessment as well as the 6 month and 12 month follow up assessments (b = −.221, t(153) = −2.13, p = .035), controlling for age, BMI, menopausal status, cancer stage, time since last treatment, radiation, endocrine therapy, chemotherapy, the interaction between chemotherapy and the linear trend for time, and negative affect. This effect accounted for 1% of the residual intercept variance not accounted for by other covariates in the model. In contrast to effects for high arousal positive affect, the association between low arousal positive affect and CRP remained significant in analyses that also controlled for fatigue (Table 4; b = −.217, t(152) = −2.04, p = .043). Thus, individuals with higher levels of low arousal positive affect demonstrated lower levels of CRP across the three time points independent of negative affect and fatigue (Figure 1). Low arousal positive affect at baseline was not associated with sTNF-RII or IL-1ra at baseline or prospectively at 6 and 12 month follow up assessments (p’s > .05).
Table 4.
Low Arousal Positive Affect and Related Covariates as Predictors of CRP in a Two-Level Multilevel Model using Restricted Maximum Likelihood (REML) Estimation (n = 186)
| CRP | |||
|---|---|---|---|
|
| |||
| B | SE | P value | |
| Intercept | .793 | .572 | .167 |
| Time | .088 | .074 | .235 |
| Low Arousal Positive Affect | −.217 | .106 | .043 |
| Negative Affect | −.017 | .017 | .326 |
| Age | −.013 | .016 | .424 |
| Body Mass Index (BMI) | .114 | .016 | <.001 |
| Fatigue Severity | .010 | .043 | .811 |
| Cancer Stage | |||
| I | .404 | .290 | .166 |
| II | .538 | .343 | .120 |
| III | 1.134 | .425 | .009 |
| Menopausal Status | |||
| (Post-menopausal before cancer is reference group) | |||
| Premenopausal | −.598 | .273 | .030 |
| Treatment-induced Menopause | −.427 | .289 | .141 |
| Months since Last Treatment | −.078 | .095 | .413 |
| Radiation Therapy | −.081 | .217 | .709 |
| Endocrine Therapy | −.317 | .109 | .004 |
| Chemotherapy | −.235 | .263 | .374 |
| Time*Chemotherapy | −.212 | .088 | .017 |
Figure 1.
Relationship of Low Arousal Positive Affect with CRP in the Year after Breast Cancer Treatment.
Note: PA = positive affect. Mean CRP shown at each tertile of low arousal positive affect for the three assessment time points. Error bars represent standard errors.
Discussion
The aim of the current study was to determine the prospective association of high and low arousal positive affect with downstream markers of inflammation in women who had recently completed primary treatment for early stage breast cancer. We found that higher levels of high arousal positive affect (“excited,” “active,” “alert,” “enthusiastic”) predicted lower levels of the soluble tumor necrosis factor receptor type II (sTNF-RII), a marker of TNF activity, one month after primary treatment completion and at 6 and 12-month follow-ups, consistent with hypotheses. Importantly, effects of high arousal positive affect were observed in analyses controlling for negative affect, indicating that the effects of high arousal positive affect are independent of negative affect and are not merely driven by the absence of negative affect. However, the relationship of high arousal positive affect with sTNF-RII did not hold over and above fatigue, suggesting that the association between sTNF-RII and high arousal positive affect may be primarily driven by the “arousal” component of this affective state. There was no association between high arousal positive affect and the other inflammatory markers assessed (i.e., CRP and IL-1RA).
A different pattern of results emerged for low arousal positive affect. Specifically, we found that low arousal positive affect (“calm,” “relaxed”) predicted lower levels of C-reactive protein (CRP) one month after primary treatment completion and at 6 and 12-month follow-ups. The relationship of low arousal positive affect and CRP remained significant in analyses controlling for negative affect and fatigue, indicating that low arousal positive affect may have distinct associations with CRP (despite being significantly negatively correlated with fatigue, similar to high arousal positive affect). There was no association with between low arousal positive affect and either sTNF-RII or IL-1RA.
Previous research in non-cancer samples has provided some support for the relationship of positive affect with reduced inflammation, including lower circulating levels of IL-6 and CRP (18) as well as lower reactivity and more efficient recovery of fibrinogen in response to a stress task (19). However, these studies aggregated ecological momentary assessments of participants’ endorsement of feeling “happy” and therefore did not examine differences between low and high arousal positive affect. Other studies which have produced mixed results for the association of positive affect and inflammation have employed measures that either do not capture level of arousal (22), or primarily capture high arousal positive affect (48, 20, 21). Although research investigating differences in the association of high versus low arousal positive affect with inflammatory processes is lacking, previous studies examining the differential effects of high versus low arousal positive affect on other immune and physiological processes have also produced somewhat mixed results (4,27–31).
Our results indicate that high and low arousal positive affect have distinct inflammatory correlates, with implications for underlying pathways. Specifically, our finding that the association between high arousal positive affect and levels of sTNF-RII was accounted for by fatigue may suggest a “sickness behavior” pathway for these effects. It is well documented that proinflammatory cytokines act on the brain and can induce a specific constellation of behavioral symptoms termed sickness behavior (49, 50), including fatigue. We have previously shown that elevated levels of sTNF-RII are associated with fatigue in a subsample of participants from the current study (35) and in another samples of breast cancer survivors (51). Thus, it is possible that the inverse association of high arousal positive affect with sTNF-RII in this study may reflect higher levels of inflammation acting on the brain-- leading to both greater fatigue and lower high arousal positive affect. Indeed, the induction of inflammatory cytokines leads to reductions in high arousal positive affect, in addition to fatigue (52).
On the other hand, the finding that low arousal positive affect was associated with lower levels of CRP, controlling for fatigue, may suggest a different underlying mechanism. States of low arousal positive affect are associated with dampened sympathetic activation, which in turn modulates inflammatory activity. It is plausible that lower arousal positive affect exerts an influence on CRP by reducing engagement of stress-response systems, which would explain the current pattern of results. Indeed, individuals who are under chronic stress show elevated levels of CRP (53–55), whereas interventions, such as mindfulness meditation, yoga, and Qigong, that cultivate positively-valenced low arousal affective states (e.g., calmness, relaxation) have been shown to specifically reduce CRP (56). Furthermore, these mind-body interventions are also associated with decreases in inflammatory markers in cancer patients and survivors (57–61; for review see 62). The specific mechanisms through which high versus low arousal positive affect are linked with inflammatory processes is an important question for future research.
Understanding the association of positive affect with inflammation is particularly important in the breast cancer context. Evidence suggests that low grade inflammation is associated with cancer-related fatigue (35,51), depression (36,37), and health comorbidities like cardiovascular disease (38) that are elevated in breast cancer survivors and negatively impact quality of life. Furthermore, although survival rates for women with early-stage disease are high, there is evidence that high levels of CRP are associated with increased risk of all-cause mortality and breast cancer-specific mortality in early-stage breast cancer survivors (34). To the extent that low arousal positive affective states are associated with lower levels of CRP in breast cancer survivors, strategies to enhance these affective states may have implications for their health and well-being, though the association with CRP was quite small.
Our results identified distinct inflammatory markers associated with high and low positive affect, as well as non-significant findings for several markers. Although inflammatory markers are often correlated, it is possible for markers to have distinct associations with the central nervous system (CNS), psychological states, and physical health, as observed in the current study. For example, sTNF-RII, but not IL-6, has been previously correlated with stress-induced changes in the CNS (63); CRP, but not IL-6 was correlated with daily family assistance in a sample of adolescents (64); and sTNF-RII has been shown to predict heart disease independent of CRP (65). Nevertheless, it is important to note that high and low arousal positive affect were each uniquely associated with only one inflammatory marker in this sample, and that several relationships we examined were non-significant (i.e., high arousal positive affect with CRP and IL-1ra and low arousal positive affect with sTNF-RII and IL-1ra). These specific effects were not predicted, but are consistent with other findings from this sample. In particular, we have shown a specific association between fatigue and levels of sTNF-RII (35), which was not observed for other circulating markers. It is possible that activation of TNF may have particular relevance for neural processes related to arousal. Given the mixed nature of our results, these findings require replication in future research, with more focused investigation of the pathways linking behavioral states with specific inflammatory processes.
Other limitations of this study include the relatively homogenous patient population in terms of racial/ethnic composition and socioeconomic status, which limits the generalizability of the results. Furthermore, in addition of level of arousal, other dimensions of positive affect may also be important to disentangle. In particular, hedonic versus eudaimonic positive affect have been associated with differing inflammatory gene expression profiles in leukocytes from healthy individuals (66), and may also have differential effects on inflammatory biology in cancer survivors. While consistent with previous research, a major limitation of the current study is the use of abbreviated versions of positive affect subscale of the PANAS (32) and serenity subscale of the PANAS-X (42) that have not been validated, therefore it is important that future research include a more focused assessment of high and low arousal positive affect using validated measures. Furthermore, much of the literature on positive affect and health focuses on the concept of happiness (67–71), which could be considered mid arousal positive affect and is not included in either one of our measures. Future research should contrast the effects of high, mid, and low arousal positive affect on immune processes. Because our study was observational in nature, we cannot draw conclusions regarding the direction of causality. Furthermore, it would be informative to have pre-treatment measures of positive affect and inflammation to further probe the temporal dynamics of these systems and their interactions before, during, and after cancer treatment.
Our results indicate that the relationship of high arousal positive affect (e.g., “excited,” “active,” “alert,” “enthusiastic”) with sTNF-RII may be driven by the overlap of high arousal positive affect with fatigue while the association of low arousal positive affect (“calm,” “relaxed”) and CRP may be unique. Of note, high and low arousal positive affect were each uniquely associated with one inflammatory marker and several of the relationships we examined were non-significant, therefore these results await replication. Future research should consider affective arousal when examining the association of positive affect with inflammation as this facet of positive affect may have important implications for interpretation of results (particularly when employing the commonly-used positive affect subscale of the PANAS; 32). Specifically, bidirectional associations between both high and low arousal positive affect and inflammation should be considered and is an important topic for future research.
Acknowledgments
Source of Funding: Research supported by the National Cancer Institute (R01 CA 109650) and the Breast Cancer Research Foundation. Patricia I. Moreno was supported through a National Institute of General Medical Sciences Training Grant (5T32GM084903).
Abbreviations
- TNF
tumor necrosis factor
- sTNF-RII
soluble tumor necrosis factor receptor type II
- IL-1ra
interleukin-1 receptor antagonist
- CRP
C-reactive protein
Footnotes
Conflicts of Interest: None of the authors have any conflicts of interest to declare.
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