Association of systemic inflammation with posttraumatic stress disorder after a myocardial infarction.

Background: Adverse mental health conditions including depression, posttraumatic stress disorder (PTSD), and anxiety are prevalent among patients who survive myocardial infarctions (MI) and are associated with adverse outcomes. The mechanisms underlying these associations, however, are not well understood. Inflammatory pathways may mediate the cardiovascular outcomes of patients with mental health disorders. We examined the bidirectional association between PTSD symptoms and inflammatory biomarkers in a young/middle-aged post MI population. We further examined how this association may differ between women and men as well as between Black and non-Black individuals. Methods: Participants included individuals with early onset MI between the ages 25 and 60. Mental health scores for depression, PTSD, perceived stress, and anxiety as well as inflammatory biomarkers, interleukin-6 (IL-6) and high sensitivity C-reactive protein (hsCRP), were collected at baseline and at six-month follow up. We examined the bidirectional changes in mental health symptoms and inflammatory biomarkers between baseline and follow-up. Results: Among 244 patients in the study (mean age: 50.8, 48.4% female, 64.3% Black), the geometric means for IL-6 level and hsCRP at rest were 1.7 pg/mL and 2.76 mg/L, respectively. Mental health scores at baseline did not consistently predict changes in inflammatory biomarkers at follow-up. However, baseline levels of both IL-6 and hsCRP were robustly associated with an increase in re-experiencing PTSD symptoms at 6 months: in adjusted linear mixed models, there was a 1.58-point increase in re-experiencing PTSD symptoms per unit of baseline hsCRP (p = 0.01) and 2.59-point increase per unit of baseline IL-6 (p = 0.02). Once the analysis was stratified by race, the association was only noted in Black individuals. Baseline inflammation was not associated with change in any of the other mental health symptom scores. Conclusion: Markers of inflammation are associated with an increase in post-event PTSD symptoms in younger or middle-aged patients who experienced an MI, especially Black patients. These results suggest a mechanistic link between inflammation and the development of PTSD among individuals with cardiovascular disease.

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.

Effect of meditation on endothelial function in Black Americans with metabolic syndrome: a randomized trial.

OBJECTIVES: Psychological stress may play a role in metabolic syndrome. A consequence of metabolic syndrome is endothelial dysfunction, which is also influenced by psychological stress. We sought to compare the effect of consciously resting meditation (CRM), a sound based meditation, with a control intervention of health education (HE) on endothelial function in the setting of metabolic syndrome. METHODS: Sixty-eight black Americans with metabolic syndrome risk factors (age, 30-65 years) were randomized to either CRM (n = 33) or HE (n = 35); interventions were matched for frequency and duration of sessions and lasted 12 months. Endothelial function was assessed by brachial artery flow-mediated dilation at baseline and at 6 and 12 months. Arterial elasticity, metabolic risk factors, and psychosocial and behavioral variables were secondary end points. RESULTS: Although flow-mediated dilation improved in the CRM group for 12 months, this increase was not significantly higher than that in the HE group (p = .51 for the interaction between group and time). Non-endothelium-dependent dilation and arterial elasticity did not change in either group. Most metabolic syndrome risk factors showed beneficial trends in the CRM group only. A risk factor score counting the number of metabolic syndrome components decreased in the CRM group only (p = .049 for the interaction between treatment group and time). CONCLUSIONS: Among black Americans with metabolic syndrome risk factors, CRM, did not improve endothelial function significantly more than a control intervention of HE. CRM resulted in favorable trends in metabolic syndrome risk factors, which were examined as secondary outcomes.

Body mass index, leptin, and ambulatory blood pressure variability in healthy adults.

OBJECTIVE: To investigate the association between body mass index (BMI) and 24-h ambulatory blood pressure (ABP) variability, and to assess whether leptin might act as a mediator of this association. METHODS: A cross-sectional study in healthy, normotensive men and women (n = 156). BMI was derived from direct height and weight measurements made on each participant. All participants underwent 24-h ABP monitoring, and two measures of ABP variability were derived--the weighted standard deviation (wSD) and the average real variability (ARV). Plasma leptin was measured using an enzyme lined immunosorbant assay. RESULTS: In linear regression models adjusted for demographic factors, glucose, creatinine, lipids, and mean ABP, BMI showed positive and statistically significant associations with diastolic wSD, and systolic and diastolic ARV. For those in the low, intermediate, and high BMI groups, mean values for diastolic wSD were 7.7, 7.9, and 8.5 mmHg, respectively (p = .02); mean values of systolic ARV were 8.2, 8.2, and 9.0 mmHg, respectively (p=.02); and mean values of diastolic ARV were 6.7, 7.0, and 7.5 mmHg, respectively (p = .01). Similarly, leptin showed positive and statistically significant associations with measures of wSD and ARV. When BMI was entered as an ordinal variable in regression models for wSD and ARV, adjustment for leptin attenuated significant ordinal BMI coefficients by as much as 60%, suggesting a mediating role for leptin. CONCLUSION: In healthy adults, BMI and leptin show positive associations with ABP variability, and leptin may play a mediating role in this association.

Relationship of self-reported alcohol consumption to ambulatory blood pressure in a sample of healthy adults.

BACKGROUND: Habitual alcohol consumption has shown positive associations with office blood pressure (BP). Less well established, however, is alcohol consumption's relationship to various measures of ambulatory BP (ABP) in healthy, normotensive persons. METHODS: We investigated alcohol consumption's relationship to mean ABP, ABP variability, and the ABP arterial stiffness index in a sample of nonsmoking adults who were free of hypertension and cardiovascular disease (CVD; n = 157). Total alcohol consumption, intake of specific alcoholic beverages, and binge drinking were assessed by self-report. ABP was measured every 30 min for 24 h. RESULTS: In multivariable-adjusted linear regression models, higher levels of total weekly alcohol consumption were associated with higher ABP. For those consuming 0, 1-2, and 3 or more alcoholic drinks per week, mean 24-h systolic ABP values were 112.2, 115.2, and 116.6 mm Hg, respectively (P = 0.05), and mean 24-h diastolic ABP values were 70.6, 71.9, and 74.2 mm Hg, respectively (P = 0.02). Beer and liquor consumption showed stronger positive associations with ABP than did wine consumption. Among nonbinge drinkers and binge drinkers, mean 24-h systolic ABP values were 113.3 and 118.6 mm Hg, respectively (P = 0.04) and mean 24-h diastolic ABP values were 71.3 and 75.0 mm Hg, respectively (P = 0.04). Alcohol consumption was not significantly related to ABP variability or the ABP arterial stiffness index. CONCLUSION: Total habitual alcohol consumption, consumption of specific alcoholic drinks, and binge drinking are associated with higher mean ABP in healthy, normotensive adults.

Common genes contribute to depressive symptoms and heart rate variability: the Twins Heart Study.

Depression and reduced heart rate variability (HRV) are predictors of coronary artery disease (CAD), and highly correlated with each other. However, little is known to what extend this correlation can be explained by common genetic components. We examined 198 middle-aged male twins (121 monozygotic and 77 dizygotic) from the Vietnam Era Twin Registry. Current depressive symptoms were assessed using the Beck Depression Inventory-II and HRV was assessed on 24-hour electrocardiographic Holter recordings. Five frequency domain variables were used, including ultra low frequency (ULF), very low frequency (VLF), low frequency (LF), high frequency (HF) and total power (TPow). Structural equation modeling was used to estimate shared genetic effects for depressive symptoms and the HRV frequency domains. Both depressive symptoms (h(2)=.5) and all measurements of HRV showed high heritability (h(2)=.43-.63). A significant inverse correlation was found between depressive symptoms and all HRV indices except LF and HF, with the highest coefficient (r) for TPow (r = -.24, P = .01) and ULF (r = -.24, P = .01). Bivariate genetic modeling revealed significant genetic correlations between depressive symptoms and TPow (r(A) = -.21, P = .04), as well as ULF (r(A) = -.23, P = .02). Of the total covariance between depressive symptoms and these two HRV indices, over 80% was due to the same genetic factors. In conclusion, depressive symptoms are associated with decreased HRV and this association is due, in large part, to a shared genetic effect. These results suggest that a common neurobiological dysfunction links depression and autonomic dysregulation.

Major depression and coronary flow reserve detected by positron emission tomography.

BACKGROUND: Major depressive disorder (MDD) is associated with coronary heart disease (CHD), but the mechanisms are unclear. The presence of MDD may increase CHD risk by affecting microvascular circulation. It is also plausible that genetic factors influencing MDD may overlap with those for CHD. We sought to examine the relationship between MDD and coronary flow reserve (CFR), the ratio of maximum flow during stress to flow at rest measured in milliliters per minute per gram of tissue. METHODS: We examined 289 male middle-aged twins, including 106 twins (53 twin pairs) discordant for a lifetime history of MDD and 183 control twins (unrelated to any twins in the experimental group) without MDD. To calculate CFR, we used positron emission tomography with nitrogen 13 ((13)N) ammonia to evaluate myocardial blood flow at rest and after adenosine stress. A standard perfusion defect score was also used to assess myocardial ischemia. RESULTS: There was no difference in myocardial ischemia between twins with and without MDD. Among the dizygotic twin pairs discordant for MDD, the CFR was 14% lower in the twins with MDD than in their brothers without MDD (2.36 vs 2.74) (P = .03). This association was not present in the monozygotic discordant pairs who were genetically matched (2.86 vs 2.64) (P = .19). The zygosity-MDD interaction after adjustment was significant (P = .006). The CFR in the dizygotic twins with MDD was also lower than in the control twins. CONCLUSIONS: Our results provide evidence for a shared genetic pathway between MDD and microvascular dysfunction. Common pathophysiologic processes may link MDD and early atherosclerosis.

Common genetic contributions to depressive symptoms and inflammatory markers in middle-aged men: the Twins Heart Study.

OBJECTIVE: To examine the extent to which a common genetic pathway is also involved in the relationship between depressive symptoms, in the absence of major depressive disorder (MDD), and inflammation. Recent data suggested that MDD and inflammation share common genes. METHODS: We recruited 188 male twins from the Vietnam Era Twin Registry who were free of symptomatic coronary artery disease and MDD, with mean +/- standard deviation (SD) age of 55 +/- 2.75 years, including 54 monozygotic and 40 dizygotic twin pairs. These pairs were assessed for two inflammatory markers, interleukin (IL)-6 and C-reactive protein (CRP). Current depressive symptoms were measured with the Beck Depression Inventory-II. Generalized estimating equations were used to examine the phenotypic association between depression and inflammatory markers. Biometrical genetic modeling was performed to estimate the genetic and environmental contributions to this association. RESULTS: An association was observed between severity of current depressive symptoms and increased levels of inflammatory markers (p < .001 for IL-6 and p = .005 for CRP). After adjustment for other factors, the association was slightly attenuated but remained statistically significant for IL-6 (p = .002). The heritability of IL-6, CRP, and depressive symptoms were estimated as 0.37, 0.65, and 0.48, respectively. Genetic modeling found a significant genetic correlation between IL-6 and depressive symptoms (r(G) = 0.22, p = .046), indicating that about 66% of the covariance between them can be explained by shared genetic influences. CONCLUSIONS: Current depressive symptoms are significantly correlated with inflammatory markers. This covariation is due, in large part, to genes that are common to depressive symptoms and inflammation.

Depressive symptoms and metabolic syndrome: is inflammation the underlying link?

BACKGROUND: Behavioral alterations, including depression, are frequent in individuals with the metabolic syndrome (MetS). Recent findings suggest that chronic activation of innate immunity might be involved. The objective of this study was to examine the relationship between MetS and depressive symptoms and to elucidate the involvement of inflammation in this relationship. METHODS: Participants were 323 male twins, with and without MetS and free of symptomatic cardiovascular disease, drawn from the Vietnam Era Twin Registry. Depressive symptoms were measured with the Beck Depression Inventory (BDI). Inflammatory status was assessed using C-reactive protein (CRP) and interleukin-6 (IL-6); twins with both CRP and IL-6 levels above the median were classified as having an elevated inflammatory status. Factor analysis was performed on individual BDI items to extract specific symptom dimensions (neurovegetative, mood, affective-cognitive). RESULTS: Subjects with MetS had more depressive symptoms than those without. Depressive symptoms with neurovegetative features were more common and more robustly associated with MetS. Both the BDI total score and each symptom subscore were associated with inflammatory biomarkers. After adjusting for age, education, and smoking status, the MetS was significantly associated with the BDI total score and the neurovegetative score. After further adjusting for inflammation, the coefficient for MetS decreased somewhat but remained statistically significant for the BDI neurovegetative subscore. When controlling for the MetS, inflammation remained significantly associated with the BDI mood subscore. CONCLUSIONS: The MetS is associated with higher depressive symptomatology characterized primarily by neurovegetative features. Inflammation is one determinant of depressive symptoms in individuals with MetS.

Depressive symptoms and heart rate variability: evidence for a shared genetic substrate in a study of twins.

OBJECTIVE: To clarify the relationship between depression and heart rate variability (HRV) in a sample of twins. Reduced HRV, a measure of autonomic dysfunction, has been linked to depression but many studies have inadequately controlled for familial and environmental factors. Furthermore, little is known about whether depression and HRV share common genetic pathways. METHODS: We performed power spectral analysis on 24-hour ambulatory electrocardiograms in 288 middle-aged male twins. Log-normalized ultra low, very low, low, high frequency, and total power were calculated. A lifetime history of major depressive disorder (MDD) was determined, using the Structured Clinical Interview for Psychiatry Disorders, and current depressive symptoms were measured with the Beck Depression Inventory. Mixed-effect regression models were used to account for intrapair variability and estimate within-pair effects at the same time controlling for potential confounders. RESULTS: Both current depressive symptoms and a history of MDD were significantly associated with lower HRV. There was a graded effect, and power in each frequency band was 29% to 36% lower in the lowest band compared with the highest BDI category. All HRV measures except high frequency remained significantly associated with current depressive symptoms in multivariable analysis, but not with lifetime history of MDD. When analyses were stratified by zygosity, a significant within-pair association between BDI score and HRV was found in the dizygotic but not in the monozygotic twins, suggesting a genetic influence on the association. CONCLUSIONS: A shared, genetically influenced biological pathway underlies the association between depression and lower HRV. These two phenotypes may be the expression of a generalized neurobiological perturbation.

Association of major depressive disorder with serum myeloperoxidase and other markers of inflammation: a twin study.

BACKGROUND: Major depressive disorder (MDD) has been linked to inflammation, but this association may be due to common precursors to both depression and inflammation. Myeloperoxidase (MPO) is an inflammatory enzyme produced by activated leukocytes that predicts risk of coronary heart disease. We sought to examine whether MPO and other markers of inflammation are associated with MDD and whether the association is confounded by genetic or other shared familial factors. METHODS: We examined 178 monozygotic and dizygotic middle-aged male twin pairs. We assessed MDD with the Structured Clinical Interview for DSM-IV. Blood markers of inflammation included MPO, interleukin-6, white blood cell count, C-reactive protein, tumor necrosis factor (TNF)-alpha, the TNF-alpha soluble receptor II, and fibrinogen. Analyses were conducted in the overall sample and among 67 twin pairs discordant for MDD using mixed effects regression. RESULTS: Twins with a history of MDD had 32% higher levels of MPO (p < .0001); this difference persisted after adjusting for other risk factors. Among dizygotic MDD-discordant twin pairs, twins with MDD had 77% higher MPO than their brothers without MDD, after adjusting for other factors (p < .0001). In contrast, no significant association was found in monozygotic twins (p = .13). Similar, but weaker, associations were found between MDD and other inflammatory biomarkers. CONCLUSIONS: Myeloperoxidase is a useful biomarker of immune activation in MDD. However, the association between inflammation and MDD is largely due to common genetic liability. Our results are consistent with the hypothesis that genes promoting inflammation are involved in the pathogenesis of MDD.

Genetic and environmental influences on systemic markers of inflammation in middle-aged male twins.

OBJECTIVES: The aims of this study were to determine the relative influence of genetic and environmental contributions to inflammatory biomarkers, and to what extent correlations among these markers are due to genetic or environmental factors. METHODS: We performed univariate and multivariate genetic analyses of four inflammatory markers: interleukin-6 (IL-6), soluble IL-6 receptor (sIL-6R), C-reactive protein (CRP), and fibrinogen, in 166 (88 monozygotic and 78 dizygotic) middle-aged male twin pairs. RESULTS: The mean age (+/-S.D.) of the twins was 54 (+/-2.93) years. Heritability was substantial for CRP (0.61, 95% CI: 0.47-0.72) and moderate to fair for IL-6 (0.31, 0.13-0.46), sIL-6R (0.49, 0.30-0.76) and fibrinogen (0.52, 0.34-0.65). IL-6, CRP and fibrinogen showed significant correlations, but not with sIL-6R. Multivariate genetic analysis found that these correlations could be best explained by a common pathway model, where the common factor explained 27%, 73% and 25% of the variance of IL-6, CRP and fibrinogen, respectively. About 46% (95% CI: 21-64%) of the correlations among the three inflammatory markers could be explained by the genetic factors. After adjusting for covariates known to influence inflammation levels, heritability estimates were slightly decreased but the overall results remained similar. CONCLUSIONS: A significant part of the variation in inflammatory marker levels is due to genetic influences. Furthermore, almost 50% of the shared variance among these biomarkers is due to a common genetic factor which likely plays a key role in the regulation of inflammation.

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.

Reduced 6-month resource use and costs associated with cilostazol in patients after successful coronary stent implantation: results from the Cilostazol for RESTenosis (CREST) trial.

BACKGROUND: The CREST trial demonstrated that after successful coronary stent implantation, the 6-month rate of target vessel revascularization (TVR) was similar (15.4% vs 16%, P = .90) for the 2 treatment groups, but restenosis rate was lower (22.0% vs 34.5%, P = .002) in cilostazol-treated patients. We sought to evaluate resource use, cost, and cost-effectiveness of cilostazol in CREST. METHODS: A total of 705 patients were randomized to cilostazol 100 mg twice daily (n = 354) versus placebo (n = 351) for 6 months. Resources included rehospitalizations, medications, and outpatient services. Costs were determined from the Medicare fee schedule. Cilostazol was priced at 1.64 dollars a day. Base-case cost and cost-effectiveness analysis was performed for the entire population using TVR as a measure of effectiveness. Sensitivity analysis was conducted among 526 patients because restenosis data were available only for this patient population. A bootstrap resample approach (5000 samples) was used to obtain confidence intervals for cost differences. RESULTS: For the entire population, costs of rehospitalizations, concomitant medications, outpatient tests, and physician or emergency department visits were lower during follow-up for cilostazol-treated patients. Overall, total 6-month follow-up costs remained 447 dollars lower for cilostazol (4178 dollars vs 4625 dollars), although this difference did not reach significance (95% CI -1458 dollars to 515 dollars). Cilostazol is likely a cost-saving strategy (similar rate of TVR and lower costs). Sensitivity analysis showed that cilostazol is likely a dominant strategy (lower restenosis rate and costs, 85% dominant, 88.9% <1000 dollars per restenosis averted). CONCLUSIONS: Treatment with cilostazol is likely a cost-saving or dominant strategy in patients with successful coronary bare metal stent implantation. Cilostazol may offer a low-cost alternative to restenosis prevention in patients who do not receive drug-eluting stents.

Relation of C-reactive protein and tumor necrosis factor-alpha to ambulatory blood pressure variability in healthy adults.

Elevated blood pressure (BP) variability has been linked to an increased risk for adverse cardiovascular events, but the biologic factors that promote elevated BP variability are not entirely understood. This cross-sectional study examined whether inflammatory factors might be associated with elevated BP variability during 24-hour ambulatory BP monitoring. Subjects were 140 healthy, normotensive adults. Inflammatory markers included C-reactive protein (CRP) and tumor necrosis factor-alpha. BP variability was calculated as the within-subject SD of BP values obtained during the daytime, nighttime, and 24-hour periods. In linear regression models that were adjusted for mean BP and other factors, CRP quartiles were positively associated with daytime systolic BP variability; for subjects in the lowest to highest CRP quartiles, the mean within-subject SDs of daytime systolic BP were 9.31, 9.62, 10.55, and 11.17, respectively (p for linear trend = 0.001). CRP showed similar positive associations with nighttime and 24-hour systolic BP variability. In contrast, tumor necrosis factor-alpha was not independently associated with systolic BP variability during any of the time periods. With respect to diastolic BP variability, significant positive associations were found between CRP and diastolic BP variability during all time periods and between tumor necrosis factor-alpha and daytime diastolic BP variability. In conclusion, there are positive associations between markers of inflammation and BP variability in healthy, normotensive adults, suggesting that inflammation may be 1 of the factors that promotes increased BP variability.