Lucy Shallenberger

Adherence to the Mediterranean Diet Is Inversely Associated With Circulating Interleukin-6 Among Middle-Aged Men: A Twin Study

Background— The Mediterranean diet is protective against cardiovascular disease; a proposed mechanism is through a reduction in systemic inflammation. It is unknown to what extent the association between the Mediterranean diet and inflammation is due to genetic or other familial factors. Methods and Results— We administered the Willett food frequency questionnaire to 345 middle-aged male twins and assessed adherence to the Mediterranean diet using a published adherence score. Fasting plasma levels of interleukin-6, C-reactive protein, and known cardiovascular risk factors were measured. Mixed-effect regression analyses were used to examine the relationship between diet score and inflammatory biomarkers after accounting for known cardiovascular risk factors. Adherence to the Mediterranean diet was associated with reduced levels of interleukin-6 (P<0.001) but not C-reactive protein (P=0.10) after adjustment for total energy intake, other nutritional factors, known cardiovascular risk factors, and use of supplements and medications. When the overall association of adherence to the diet with interleukin-6 levels was partitioned into between- and within-pair effects, the between-pair effect was not significant (P=0.9) and the within-pair effect was highly significant (P<0.0001). A 1-unit within-pair absolute difference in the diet score was associated with a 9% (95% CI, 4.5 to 13.6) lower interleukin-6 level. Conclusions— Shared environmental and genetic factors are unlikely to play a major role in the association between adherence to the Mediterranean diet and systemic inflammation. These results support the hypothesis that reduced inflammation is an important mechanism linking Mediterranean diet to reduced cardiovascular risk.

Sex-Specific Association of Depression and a Haplotype in Leukotriene A4 Hydrolase Gene

Objective: To assess whether genetic variants involved in inflammation play a role in the sex difference in depression. Depression is, in part, genetically determined and inflammation has been implicated. Women are twice as likely to develop depression as men. Methods: We examined the association, separately in men and women, between seven single nucleotide polymorphisms (SNPs) in the arachidonate 5-lipoxygenase-activating protein (ALOX5AP) gene and 12 SNPs in the leukotriene A4 hydrolase (LTA4H) gene and depression in 1368 white subjects (30.4% female) referred for cardiovascular evaluation. Depression was defined as a score of ≥10 in the Patient Health Questionnaire 9. Single marker analysis was assessed by the &khgr;2 test. Haplotype-specific associations were performed, using likelihood ratio tests. Empirical significance levels were determined by permutation tests. Results: Depressed individuals, comprising 14.5% of the total, were more likely to be female, current smokers, have a history of diabetes and myocardial infarction. None of the SNPs in the ALOX5AP gene, either singly or in combination, was associated with depression. The 12 SNPs in the LTA4H gene were not individually associated with depression. However, a six-SNP haplotype in LTA4H gene, named HapE, showed a significant protective effect on depression in women, but not in men, after correcting for cardiovascular effects. The interaction between HapE and sex on depression was statistically significant. Conclusion: This study provides the first evidence for a sex-specific association of a novel haplotype in the LTA4H gene on depression. Although replication is needed, our study suggests that genetic variations may underlie sex differences in depression. SNPs = single nucleotide polymorphisms; ALOX5AP = arachidonate 5-lipoxygenase-activating protein; LTA4H = leukotriene A4 hydrolase; CAD = coronary artery disease; PHQ9 = Patient Health Questionnaire 9.

Association between anger and mental stress–induced myocardial ischemia

BACKGROUND Mental stress-induced myocardial ischemia is associated with adverse prognosis in coronary artery disease patients. Anger is thought to be a trigger of acute coronary syndromes and is associated with increased cardiovascular risk; however, little direct evidence exists for a link between anger and myocardial ischemia. METHODS [(99m)Tc]-sestamibi single-photon emission tomography was performed at rest, after mental stress (a social stressor with a speech task) and after exercise/pharmacologic stress. Summed scores of perfusion abnormalities were obtained by observer-independent software. A summed-difference score, the difference between stress and rest scores, was used to quantify myocardial ischemia under both stress conditions. The Spielbergers State-Trait Anger Expression Inventory was used to assess different anger dimensions. RESULTS The mean age was 50 years, 50% were female, and 60% were non-white. After adjusting for demographic factors, smoking, coronary artery disease severity, depressive, and anxiety symptoms, each IQR increment in state-anger score was associated with 0.36 U-adjusted increase in ischemia as measured by the summed-difference score (95% CI 0.14-0.59); the corresponding association for trait anger was 0.95 (95% CI 0.21-1.69). Anger expression scales were not associated with ischemia. None of the anger dimensions was related to ischemia during exercise/pharmacologic stress. CONCLUSION Anger, both as an emotional state and as a personality trait, is significantly associated with propensity to develop myocardial ischemia during mental stress but not during exercise/pharmacologic stress. Patients with this psychologic profile may be at increased risk for silent ischemia induced by emotional stress, and this may translate into worse prognosis.

Depressive symptoms are associated with mental stress-induced myocardial ischemia after acute myocardial infarction.

Objectives Depression is an adverse prognostic factor after an acute myocardial infarction (MI), and an increased propensity toward emotionally-driven myocardial ischemia may play a role. We aimed to examine the association between depressive symptoms and mental stress-induced myocardial ischemia in young survivors of an MI. Methods We studied 98 patients (49 women and 49 men) age 38–60 years who were hospitalized for acute MI in the previous 6 months. Patients underwent myocardial perfusion imaging at rest, after mental stress (speech task), and after exercise or pharmacological stress. A summed difference score (SDS), obtained with observer-independent software, was used to quantify myocardial ischemia under both stress conditions. The Beck Depression Inventory-II (BDI-II) was used to measure depressive symptoms, which were analyzed as overall score, and as separate somatic and cognitive depressive symptom scores. Results There was a significant positive association between depressive symptoms and SDS with mental stress, denoting more ischemia. After adjustment for demographic and lifestyle factors, disease severity and medications, each incremental depressive symptom was associated with 0.14 points higher SDS. When somatic and cognitive depressive symptoms were examined separately, both somatic [β = 0.17, 95% CI: (0.04, 0.30), p = 0.01] and cognitive symptoms [β = 0.31, 95% CI: (0.07, 0.56), p = 0.01] were significantly associated with mental stress-induced ischemia. Depressive symptoms were not associated with ischemia induced by exercise or pharmacological stress. Conclusion Among young post-MI patients, higher levels of both cognitive and somatic depressive symptoms are associated with a higher propensity to develop myocardial ischemia with mental stress, but not with physical (exercise or pharmacological) stress.

High habitual dietary α-linolenic acid intake is associated with decreased plasma soluble interleukin-6 receptor concentrations in male twins

BACKGROUND alpha-Linolenic acid (ALA) is associated with a low risk of cardiovascular disease; however, the underlying mechanism is not completely known. OBJECTIVE The objective was to examine whether habitual dietary ALA intake is associated with plasma concentrations of inflammatory biomarkers after control for shared genetic and common environmental factors. DESIGN We cross-sectionally studied 353 middle-aged male twins. Habitual diet was assessed with the Willett food-frequency questionnaire. Fasting plasma concentrations of interleukin-6 (IL-6) and its soluble receptor (sIL-6R), high-sensitivity C-reactive protein (hsCRP), and tumor necrosis factor-alpha (TNF-alpha) were measured. Linear mixed-effect regression analysis was used to partition the overall association into within- and between-pair associations. RESULTS A 1-g increment in habitual dietary ALA intake was associated with 11.0% lower concentrations of sIL-6R (P = 0.004) but not of IL-6 (P = 0.31), TNF-alpha (P = 0.16), or hsCRP (P = 0.36) after adjustment for energy intake, nutritional factors, known cardiovascular disease risk factors, and medications. After further control for shared genetic and common environmental factors by comparison of brothers within a twin pair, a twin with a 1-g higher ALA intake was likely to have 10.9% (95% CI: 3.7%, 17.6%; P = 0.004) lower sIL-6R concentrations than his co-twin with a low intake, whereas ALA intake was not significantly associated with plasma concentrations of IL-6, TNF-alpha, or hsCRP. These results were validated by using 1000 bootstrap samples. CONCLUSIONS Habitual dietary ALA intake is inversely associated with plasma sIL-6R concentrations independent of shared genetic and common environmental influences. Lowering sIL-6R may be a mechanism underlying the cardioprotective properties of habitual dietary ALA. This study was registered at clinicaltrials.gov as NCT00017836.

Young women post-MI have higher plasma concentrations of interleukin-6 before and after stress testing.

OBJECTIVES Young women have poorer prognosis after myocardial infarction (MI) and a higher rate of mental stress-induced ischemia compared with similarly aged men. A higher inflammatory status may help explain these sex differences. METHODS We examined 98 patients (49 women and 49 men) age 18-59years with recent MI (past 6months). Women and men were matched for age, type of MI, and time since MI. Interleukin 6 (IL-6) concentrations were measured at baseline, after mental stress using a speech task, and after exercise/pharmacologic stress (60 and 90min). Depressive symptoms were measured with the Beck Depression Inventory (BDI-II) and angiographic coronary artery disease (CAD) severity was quantified with the Gensini score. Single-photon emission computed tomography (SPECT) was used to obtain a computerized measurement of stress-induced ischemia (summed difference score, or SDS) and determine whether severity of stress-induced ischemia affects the inflammatory response to stress. Analysis was stratified by the median age of 50. Geometric mean concentrations of IL-6 were obtained from general linear regression models. RESULTS In both age groups, women had less angiographic CAD and a similar level of conventional risk factors compared with men. Despite this, baseline IL-6 geometric means before both mental and physical stress were twice as high in women ⩽50years of age compared to age-matched men (3.8 vs. 1.8pg/mL, p=0.001, across both conditions), while they were similar in women and men age >50years (2.3 vs. 2.2pg/mL, p=0.83). After mental stress, IL-6 concentrations increased in both women and men in a similar fashion and remained twice as high in women ⩽50years than men at both 60min (5.4 vs. 2.6pg/mL, p=0.002) and 90min (5.9 vs. 3.4pg/mL, p=0.01). No significant difference was found between women and men >50years of age at any time point after mental stress. Results were similar for physical stress. After accounting for SDS, IL-6 concentrations in young women remained higher after both mental and physical stress. Baseline IL-6 concentrations were not significantly related to inducible ischemia. CONCLUSIONS After MI, young women aged 50years or younger, compared with age-matched men, have remarkably higher concentrations of inflammation at baseline and after both mental and physical stress, with a similar inflammatory response to both stressors. Sustained concentrations of inflammation in young women, not their response to stress, may contribute to their adverse outcomes post-MI.

Posttraumatic Stress Disorder, Combat Exposure, and Carotid Intima-Media Thickness in Male Twins

Posttraumatic stress disorder (PTSD) is associated with an increased risk of ischemic heart disease, though the pathophysiologic mechanisms remain unclear. Carotid artery intima-media thickness (CIMT) is a measure of subclinical atherosclerosis. We examined whether PTSD and combat exposure were associated with CIMT in Vietnam War-era twins after controlling for shared genetic and childhood factors. Between 2002 and 2010, we studied 465 middle-aged twins from the Vietnam Era Twin Registry who were free from cardiovascular disease. PTSD was diagnosed using the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, and CIMT was measured by ultrasound. Mixed-effects regression models were used to examine individual, between-pair, and within-pair associations. Approximately 13% of participants met the criteria for PTSD, and 45% served in the Vietnam Theater. PTSD was associated with 32.7 μm higher CIMT (95% confidence interval (CI): 0.9, 64.5) after adjustment for confounders. The average CIMT for the pair increased by 59.7 μm for each additional twin with PTSD (95% CI: 15.9, 104.2). We found no significant within-pair differences in CIMT when comparing PTSD-discordant co-twins. Results for combat exposure were similar, but its association with CIMT weakened after adjustment for PTSD (95% CI: 7.0, 45.3). Among Vietnam War-era veterans, combat exposure and PTSD are associated with CIMT, though the associations are largely mediated by shared childhood factors.

Association of Depressive Symptoms and Heart Rate Variability in Vietnam War–Era Twins: A Longitudinal Twin Difference Study

Importance Depressive symptoms are associated with lower heart rate variability (HRV), an index of autonomic dysregulation, but the direction of the association remains unclear. Objective To investigate the temporal association between depression and HRV. Design, Settings, and Participants A longitudinal, cross-lagged twin difference study, with baseline assessments from March 2002 to March 2006 (visit 1) and a 7-year follow-up (visit 2) at an academic research center with participants recruited from a national twin registry. Twins (n = 166) from the Vietnam Era Twin Registry, who served in the US military during the Vietnam War, and were discordant for depression at baseline were recruited. Main Outcomes and Measures At both visits, depressive symptoms were measured using the Beck Depression Inventory-II (BDI-II), and HRV was measured through 24-hour electrocardiogram monitoring. To assess the direction of the association, within-pair differences in multivariable mixed-effects regression models were examined, and standardized &bgr; coefficients for both pathways were calculated. The associations were evaluated separately in monozygotic and dizygotic twins. Results In the final analytic sample (N = 146), all participants were men, 138 (95%) were white, and the mean (SD) age was 54 (3) years at baseline. Results showed consistent associations between visit 1 HRV and visit 2 BDI score across all HRV domains and models (&bgr; coefficients ranging from −0.14 to −0.29), which were not explained by antidepressants or other participant characteristics. The magnitude of the association was similar in the opposite pathway linking visit 1 BDI score to visit 2 HRV, with &bgr; coefficients ranging from 0.05 to −0.30, but it was largely explained by antidepressant use. In stratified analysis by zygosity, significant associations were observed in monozygotic and dizygotic twins for the path linking visit 1 HRV to visit 2 BDI score, although the associations were slightly stronger in dizygotic twins. Conclusions and Relevance The association between depression and autonomic dysregulation, indexed by HRV, is bidirectional, with stronger evidence suggesting that autonomic function affects depression risk rather than vice versa. The opposite causal pathway from depression to lower HRV is mostly driven by antidepressant use. These findings highlight an important role of autonomic nervous system in the risk of depression and contribute new understanding of the mechanisms underlying the comorbidity of depression and cardiovascular disease.

Longitudinal Association of Inflammation with Depressive Symptoms: A 7-Year Cross-lagged Twin Difference Study

BACKGROUND The direction of the association between inflammation and depressive symptoms remains inconsistent. The objective of this study was to evaluate the temporal relationship between inflammation and depressive symptoms, and to assess the role of genetic factors on this association. METHODS In this longitudinal cross-lagged twin difference study, we examined 166 (83 pairs) middle-aged male twins recruited from the Vietnam Era Twin Registry, who were assessed at baseline and after 7 years of follow-up. We assayed plasma levels of two inflammatory biomarkers, interleukin-6 (IL-6) and high sensitivity C-reactive protein (CRP) and measured depressive symptoms using the Beck Depression Inventory-II (BDI). To evaluate the direction of the association, we constructed multivariable mixed-effects regression models and calculated standardized beta-coefficients to compare the strength of the within-pair association for both pathways. We then conducted a stratified analysis by zygosity and assessed the associations in monozygotic and dizygotic twin pairs separately. RESULTS The 166 twins were 95% white and had a mean (SD) age of 54 (3) years at baseline. The cross-lagged analysis showed significant and positive associations from visit 1 IL-6 to visit 2 BDI across all models (beta-coefficients ranging from 0.18 to 0.22). However, the opposite pathway (visit 1 BDI to visit 2 IL-6) was not significant after adjusting for confounding factors. In contrast, visit 1 BDI was significantly associated with visit 2 CRP in all models (beta-coefficients ranging from 0.23 to 0.33), while the opposite pathway (visit 1 CRP to visit 2 BDI) showed no significant association. When stratifying by zygosity, significant associations from IL-6 to depression were only seen in monozygotic twins, but associations from depression to CRP were more robust in dizygotic twins, which implies that genetic factors may play a role in this association. CONCLUSIONS The association between inflammation and depression may be bidirectional. Elevated IL-6 levels are more likely to be a risk factor of depression rather than a consequence, while the opposite may be true for elevated CRP. The biological underpinnings of these bidirectional pathways need further evaluation.