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Genetic variations affecting the course of depressive symptoms in patients with coronary artery disease (CAD) have not yet been well studied. Therefore, we set out to investigate whether distinct haplotypes of the two insertion/deletion polymorphisms in the serotonin-transporter-linked polymorphic region (5-HTTLPR) and the angiotensin I-converting enzyme (ACE) gene located on chromosome 17 can be identified as risk factors for trajectories of depression. Clinical and genotyping data were derived from 507 depressed CAD patients participating in the randomized, controlled, multicenter Stepwise Psychotherapy Intervention for Reducing Risk in Coronary Artery Disease (SPIRR-CAD) trial, of whom the majority had an acute cardiac event before study inclusion. Depression scores on the Hospital Anxiety and Depression Scale (HADS) were assessed at baseline and at five follow-up time points up to 2 years after study entrance. At baseline, depression scores did not significantly differ between patients carrying the risk haplotype ACE D/D, 5-HTTLPR I/I (n = 46) and the non-risk haplotypes (n = 461, 10.9 ± 2.7 versus 10.4 ± 2.5, p = 0.254). HADS-depression scores declined from study inclusion during the first year irrespective of the genotype. At each follow-up time point, HADS-depression scores were significantly higher in ACE D/D, 5-HTTLPR I/I carriers than in their counterparts. Two years after study inclusion, the mean HADS depression score remained 1.8 points higher in patients with the risk haplotype as compared to subjects not carrying this haplotype (9.9 ± 4.2 versus 8.1 ± 4.0, p = 0.009). In summary, the presence of the ACE D/D, 5-HTTLPR I/I haplotype may be a vulnerability factor for comorbid depressive symptoms in CAD patients.

Hostility has long been thought to play a role in health, and recent research has now documented substantial effects on disease etiology, with much of the attention given to its role in cardiovascular disease. Several measures of this construct have been found to predict adverse cardiovascular events as well as cardiac and total mortality. It is apparent, however, that the hostility construct has multiple aspects, including cynical and suspicious attitudes, various negative emotions, and antagonistic behavior patterns. Interpersonal experiences, such as child rearing patterns and adult adversity in combination with physiological and genetic factors, influence the development of these tendencies. The links to physical health appear to involve several processes such as enhanced autonomic reactivity and altered glucose metabolism that are the product of the stress associated with antagonistic experiences. In addition, high hostility is associated with a lifestyle that produces an adverse risk factor pattern. There is promising evidence in clinical samples suggesting that interventions based on coping skills training may be able to improve health through the reduction of these hostile tendencies.

OBJECTIVES: Central nervous system (CNS) serotonin (5-HT) exerts both excitatory and inhibitory effects on the sympathetic nervous system (SNS) in animals. In this study, we examine the effects of tryptophan enhancement and depletion on plasma catecholamine levels in humans. METHODS: The total sample consisted of 164 healthy men and women who were tested over 2 days. Seventy-nine participants were randomized to a tryptophan enhancement condition and eighty-five to a tryptophan depletion condition. Both protocols consisted of a “sham-day” followed by an “active-day”. Blood samples for assessment of plasma norepinephrine and epinephrine levels were collected prior and post tryptophan enhancement/depletion. Data were analyzed using general linear models. Separate analyses were conducted for each study arm and for each measure. RESULTS: In the depletion condition, both epinephrine (F(5,330) = 2.69, p = .021) and norepinephrine (F(5,335) = 2.79, p =.018) showed small increases on active vs ‘sham’ depletion days. There were also significant day X time interactions for epinephrine (F(3,171) = 39.32, p < .0001) and norepinephrine (F(3,195) = 31.09, p < .0001) levels in the enhancement arm. Tryptophan infusion resulted in a marked increase in epinephrine (Pre(mean =)23.92±12.23 vs. Post(mean =)81.57±62.36) and decrease in norepinephrine (Pre(mean =)257.2±106.11 vs. Post(mean =)177.04±87.15 ) whereas levels of both catecholamines were stable on the “sham-day”. CONCLUSIONS: CNS 5-HT exerts both inhibitory and excitatory effects on SNS activity in humans, potentially due to stimulation of CNS 5-HT receptors that have shown to have inhibitory (5-HT(1A)) and excitatory (5-HT(1A) and/or 5-HT(2)) SNS effects in animal models.

INTRODUCTION: Analyses of cerebrospinal fluid (CSF) metabolites in large, healthy populations have been limited and potential demographic moderators of brain metabolism are largely unknown. OBJECTIVE: Our objective in this study was to examine sex and race differences in 33 CSF metabolites within a sample of 129 healthy individuals (37 African American women, 29 white women, 38 African American men, and 25 white men). METHODS: CSF metabolites were measured with a targeted electrochemistry-based metabolomics platform. Sex and race differences were quantified with both univariate and multivariate analyses. Type I error was controlled for by using a Bonferroni adjustment (.05/33 = .0015). RESULTS: Multivariate Canonical Variate Analysis (CVA) of the 33 metabolites showed correct classification of sex at an average rate of 80.6% and correct classification of race at an average rate of 88.4%. Univariate analyses revealed that men had significantly higher concentrations of cysteine (p

Expression of the serotonin transporter is affected by the genotype of the 5-HTTLPR (short and long forms) as well as the genotype of the SNP rs25531 within this region. Based on the combined genotypes for these polymorphisms, we designated each allele as a high or low expressing allele according to established expression levels-resulting in HiHi, HiLo,LoLo genotype groups for analysis. We evaluated effects of gender and the promoter genotype on induction of negative affect by intravenous infusion of L: -tryptophan (TRP). The protocol consisted of a day-1 sham saline infusion and a day-2 active TRP infusion. Models assessed 5-HTTLPR composite genotype and gender as predictors of change in ratings of negative emotion during TRP infusion. During sham infusion there were no significant changes from baseline in mood ratings. During TRP infusion all negative affect ratings increased significantly from baseline (P's.02). The genotype x gender interaction was a significant predictor of depression-dejection (P = .013), and trended towards predicting anger-hostility (P = .084). Males in the HiHi group had greater increases in negative affect during infusion, compared to all groups except LoLo females, who also showed increased negative affect.

In prior work, we identified a novel gene-by-stress association of EBF1’s common variation (SNP rs4704963) with obesity (i.e., hip, waist) in Whites, which was further strengthened through multiple replications using our synthetic stress measure. We now extend this prior work in a precision medicine framework to find the risk group using harmonized data from 28,026 participants by evaluating the following: (a) EBF1 SNPxSTRESS interaction in Blacks; (b) 3-way interaction of EBF1 SNPxSTRESS with sex, race, and age; and (c) a race and sex-specific path linking EBF1 and stress to obesity to fasting glucose to the development of cardiometabolic disease risk. Our findings provided additional confirmation that genetic variation in EBF1 may contribute to stress-induced human obesity, including in Blacks (P = 0.022) that mainly resulted from race-specific stress due to “racism/discrimination” (P = 0.036) and “not meeting basic needs” (P = 0.053). The EBF1 gene-by-stress interaction differed significantly (P = 1.01e−03) depending on the sex of participants in Whites. Race and age also showed tentative associations (Ps = 0.103, 0.093, respectively) with this interaction. There was a significant and substantially larger path linking EBF1 and stress to obesity to fasting glucose to type 2 diabetes for the EBF1 minor allele group (coefficient = 0.28, P = 0.009, 95% CI = 0.07-0.49) compared with the same path for the EBF1 major allele homozygotes in White females and also a similar pattern of the path in Black females. Underscoring the race-specific key life-stress indicators (e.g., racism/discrimination) and also the utility of our synthetic stress, we identified the potential risk group of EBF1 and stress-induced human obesity and cardiometabolic disease.

A wide range of health benefits of exercise have been documented in clinical lifestyle medicine. However, many individuals fail to complete or maintain an exercise program. We hypothesized that this behavior has biological underpinnings. Thus, we conducted analyses of multi-omic data obtained from genomic, transcriptomic and metabolomic data specific to subjects (n=603) initiating a well-characterized exercise training trial (STRRIDE-Study of a Targeted Risk Reduction Intervention through Defined Exercise) to understand the biology of non-completion. GWAS detected the strongest evidence of association with non-completion was at SNP rs722069 (P = 2.2 х 10 -7 , OR=2.23, T/C, risk allele =C) on chromosome 16, with other 8 SNPs in a linkage disequilibrium block (pairwise R 2 > 0.74). These SNPs were eQTLs of the EARS2, COG7 and DCTN5 genes in skeletal muscle tissue in GTEx portal. In a subset of the STRRIDE sample, the C allele of rs722069 was associated with lower pre-exercise skeletal muscle expression of EARS2 (P < 0.016) using Affymetrix platform (n=37). This was further replicated (P=0.017) in another set of skeletal muscle expression data using the Illumina gene expression array (n=67). The C allele was associated with lower pre-exercise skeletal muscle concentrations of C2- and C3-acylcarnitines (P < 0.03) - the incomplete oxidation products of fatty acid and amino acid metabolism. Lower EARS2 skeletal muscle expression was also related to the lower C2- and C3-acylcarnitine concentrations in skeletal muscle ( P < 0.05) before exercise. Rs722069 variants were not related to maximal oxygen uptake and insulin sensitivity in the individuals completing the exercise intervention. The tests of glucose and lipids levels associated with the genetic variants in this LD block are ongoing. To further understand the systemic genetics and biology of non-completion, in silico functional analysis for the genes in this region such as UBFD1, NDUFAB1, PALB2 is also under way. Our results imply that non-completion is genetically moderated through differential gene expression and metabolic pathways in skeletal muscle. Impaired mitochondrial energetics in skeletal muscle may be partly responsible for non-completion. Individual genetic traits may allow development of a biomarker-approach to identify individuals that would benefit from more intensive counseling to maintain exercise programs.

BACKGROUND/OBJECTIVES: Although childhood attention deficit hyperactivity disorder (ADHD) has been previously associated with concurrent and later obesity in adulthood, the etiology of this association remains unclear. The objective of this study is to determine the shared genetic effects of ADHD symptoms and BMI in a large sample of sibling-pairs, consider how these shared effects may vary over time, and examine potential sex differences. SUBJECT/METHODS: Sibling-pair data was obtained from the National Longitudinal Study of Adolescent to Adult Health (Add Health); childhood ADHD symptoms were reported retrospectively during young adulthood, while three prospective measurements of BMI were available from young adulthood to later adulthood. Cholesky decomposition models were fit to this data using Mx using maximum-likelihood estimation. The twin and sibling sample for these analyses included: 221 monozygotic (MZ) pairs (92 male-male, 139 female-female), 228 dizygotic (DZ) pairs (123 male-male, 105 female-female), 471 full-sibling (FS) pairs (289 male-male, 182 female-female), 106 male-female DZ twin pairs, and 234 male-female FS pairs. RESULTS: The magnitude of the association between childhood ADHD symptoms and BMI changed over time, and by sex. The etiological relationship between childhood ADHD symptoms and the three prospective measurements of BMI differed for males and females, such that unique or non-shared environmental influences contributed to the relationship within males, and genetic factors contributed to the relationship within females. Specifically, among females, genetic influences on childhood ADHD symptoms were partially shared with those effecting BMI and increased from adolescence to later adulthood (genetic correlation = 0.20 (95% CI: 0.07–0.36) in adolescence and 0.24 (95% CI: 0.10, 0.41) in adulthood). CONCLUSION: Genetic influences on ADHD symptoms in childhood are partially shared with those effecting obesity. However, future research is needed to determine why this association is limited to females.

Objectives Among many challenges in cardiovascular disease (CVD) risk prediction are interactions of genes with stress, race, and/or sex and developing robust estimates of these interactions. Improved power with larger sample size contributed by the accumulation of epidemiological data could be helpful, but integration of these datasets is difficult due the absence of standardized phenotypic measures. In this paper, we describe the details of our undertaking to harmonize a dozen datasets and provide a detailed account of a number of decisions made in the process. Results We harmonized candidate genetic variants and CVD-risk variables related to demography, adiposity, hypertension, lipodystrophy, hypertriglyceridemia, hyperglycemia, depressive symptom, and chronic psychosocial stress from a dozen studies. Using our synthetic stress algorithm, we constructed a synthetic chronic psychosocial stress measure in nine out of twelve studies where a formal self-rated stress measure was not available. The mega-analytic partial correlation between the stress measure and depressive symptoms while controlling for the effect of study variable in the combined dataset was significant (Rho = 0.27, p

While behavioral interventions can improve blood pressure (BP) in individuals with hypertension, getting such services to people who could benefit remains difficult. Workplace programs have potential as dissemination vehicles. The objective is to evaluate the effectiveness of a standardized stress management program delivered in groups at the workplace for reducing BP compared with enhanced usual care. This randomized controlled trial studied 92 urban medical center employees with hypertension randomized into two groups. The intervention was a 10-week group workshop on cognitive-behavioral coping skills. Enhanced usual care included self-help materials for BP reduction and physician referral. Intervention group participants’ systolic BP (SBP) decreased 7.5 mm Hg over controls between baseline and follow-up, from 149.1 (95% CI: 146.0–152.1) to 140.0 (95% CI: 134.7–145.2), p < .001. The differential change between intervention and enhanced usual care groups (Group × Time interaction) was 7.5 mm Hg (t = −2.05; p = .04). Diastolic BP reductions were not significantly different. Scores on measures of emotional exhaustion and depressive rumination showed significant improvements and correlated with reductions in SBP. There was no significant change in the usual care group. A standardized worksite group intervention produced clinically meaningful reductions in SBP in participants with hypertension.

This study sought to determine the effect of a 2-year, multicomponent health intervention (Spirited Life) targeting metabolic syndrome and stress simultaneously.An RCT using a three-cohort multiple baseline design was conducted in 2010-2014.Participants were United Methodist clergy in North Carolina, U.S., in 2010, invited based on occupational status. Of invited 1,745 clergy, 1,114 consented, provided baseline data, and were randomly assigned to immediate intervention (n=395), 1-year waitlist (n=283), or 2-year waitlist (n=436) cohorts for a 48-month trial duration.The 2-year intervention consisted of personal goal setting and encouragement to engage in monthly health coaching, an online weight loss intervention, a small grant, and three workshops delivering stress management and theological content supporting healthy behaviors. Participants were not blinded to intervention.Trial outcomes were metabolic syndrome (primary) and self-reported stress and depressive symptoms (secondary). Intervention effects were estimated in 2016 in an intention-to-treat framework using generalized estimating equations with adjustment for baseline level of the outcome and follow-up time points. Log-link Poisson generalized estimating equations with robust SEs was used to estimate prevalence ratios (PRs) for binary outcomes; mean differences were used for continuous/score outcomes.Baseline prevalence of metabolic syndrome was 50.9% and depression was 11.4%. The 12-month intervention effect showed a benefit for metabolic syndrome (PR=0.86, 95% CI=0.79, 0.94, p0.001). This benefit was sustained at 24 months of intervention (PR=0.88; 95% CI=0.78, 1.00, p=0.04). There was no significant effect on depression or stress scores.The Spirited Life intervention improved metabolic syndrome prevalence in a population of U.S. Christian clergy and sustained improvements during 24 months of intervention. These findings offer support for long-duration behavior change interventions and population-level interventions that allow participants to set their own health goals.This study is registered at www.clinicaltrials.gov NCT01564719.

Objective Depressive symptoms have been associated with myocardial ischemia induced by mental (MSIMI) and exercise (ESIMI) stress in clinically stable ischemic heart disease (IHD) patients, but the association between positive emotions and inducible ischemia is less well characterized. The objective of this study was to examine the associations between ratings of well-being and stress-induced ischemia. Methods Subjects were adult patients with documented IHD underwent mental and exercise stress testing for the Responses of Myocardial Ischemia to Escitalopram Treatment (REMIT) trial. The General Well-Being Schedule (GWBS), with higher scores reflecting greater subjective well-being, and the Center for Epidemiologic Studies Depression Scale (CES-D) were obtained from the REMIT participants. Echocardiography was used to measure ischemic responses to mental stress and Bruce protocol treadmill exercise testing. Data were analyzed using logistic regression adjusting for age, sex, resting left-ventricular ejection fraction (LVEF), and resting wall motion score index, as well as health-related behaviors. Results GWBS scores were obtained for 210 individuals, with MSIMI present in 92 (43.8%) and ESIMI present in 64 (30.5%). There was a significant inverse correlation between GWBS-PE (Positive Emotion subscale) scores and probability of ESIMI (OR = 0.55 (95%CI 0.36–0.83), p = 0.005). This association persisted after additional control for CESD subscales measuring negative and positive emotions and for variables reflecting health-related behaviors. A similar inverse correlation between GWBS-PE and MSIMI was observed, but did not reach statistical significance (OR = 0.81 (95%CI 0.54–1.20), p = 0.28). Conclusion This is, to our knowledge, the first study demonstrating that greater levels of self-reported positive emotions are associated with a lower likelihood of ESIMI among patients with known IHD. Our results highlight the important interface functions of the central nervous and cardiovascular systems and underscore areas for future investigation.

Aims Mental stress-induced myocardial ischemia (MSIMI) occurs in up to 70% of patients with clinically stable ischemic heart disease and is associated with increased risk of adverse prognosis. We aimed to examine the prognostic value of indices of MSIMI and exercise stress-induced myocardial ischemia (ESIMI) in a population of ischemic heart disease patients that was not confined by having a recent positive physical stress test. Methods and results The Responses of Mental Stress Induced Myocardial Ischemia to Escitalopram Treatment (REMIT) study enrolled 310 subjects who underwent mental and exercise stress testing and were followed annually for a median of four years. Study endpoints included time to first and total rate of major adverse cardiovascular events, defined as all-cause mortality and hospitalizations for cardiovascular causes. Cox and negative binomial regression adjusting for age, sex, resting left ventricular ejection fraction, and heart failure status were used to examine associations of indices of MSIMI and ESIMI with study endpoints. The continuous variable of mental stress-induced left ventricular ejection fraction change was significantly associated with both endpoints (all p values 0.05). For every reduction of 5% in left ventricular ejection fraction induced by mental stress, patients had a 5% increase in the probability of a major adverse cardiovascular event at the median follow-up time and a 20% increase in the number of major adverse cardiovascular events endured over the follow-up period of six years. Indices of ESIMI did not predict endpoints ( ps 0.05). Conclusion In patients with stable ischemic heart disease, mental, but not exercise, stress-induced left ventricular ejection fraction change significantly predicts risk of future adverse cardiovascular events.

According to a review conducted by the Duke University Office of Research, Professor Edward C. Suarez was omitted as an author in the above-cited article. The university concluded that Dr. Suarez qualifies …

Background DNA methylation is implicated in many chronic diseases and may contribute to mortality. Therefore, we conducted an epigenome‐wide association study ( EWAS ) for all‐cause mortality with whole‐transcriptome data in a cardiovascular cohort ( CATHGEN [Catheterization Genetics]). Methods and Results Cases were participants with mortality≥7 days postcatheterization whereas controls were alive with≥2 years of follow‐up. The Illumina Human Methylation 450K and EPIC arrays (Illumina, San Diego, CA) were used for the discovery and validation sets, respectively. A linear model approach with empirical Bayes estimators adjusted for confounders was used to assess difference in methylation (Δβ). In the discovery set (55 cases, 49 controls), 25 629 (6.5%) probes were differently methylated ( P P SLC 4A9 ; log 2 fold change=−0.14); cg17845532 ( MATK ; fold change=−0.26); and cg17944110 (castor zinc finger 1 [ CASZ1 ]; FC =0.26; P P =0.046–0.080). Meta‐analysis identified 6 probes (false discovery rate–adjusted P NCOR 2 ), and cg23198793 ( CAPN 3 ). Messenger RNA expression of 2 MATK isoforms was lower in cases (fold change=−0.24 [ P =0.007] and fold change=−0.61 [ P =0.009]). The CASZ 1 , NCOR 2 , and CAPN 3 transcripts did not show differential expression ( P >0.05); the SLC 4A9 transcript did not pass quality control. The cg17944110 probe is located within a potential regulatory element; expression of predicted targets (using GeneHancer) of the regulatory element, UBIAD 1 ( P =0.01) and CLSTN 1 ( P =0.03), were lower in cases. Conclusions We identified 6 novel methylation sites associated with all‐cause mortality. Methylation in CASZ 1 may serve as a regulatory element associated with mortality in cardiovascular patients. Larger studies are necessary to confirm these observations.

After the publication of the original article, the Editor was notified by Duke University that they have determined the authorship to be incomplete. Consequently, Dr Edward Suarez has been added as a co-author to represent his contribution to the conception and design of the work and acquisition of the data.

Greater optimism regarding recovery from chronic illness is associated with improved quality of life and clinical outcomes. We performed a post-hoc analysis on the association between optimism and outcomes in Ranolazine in Patients with Incomplete Revascularization after Percutaneous Coronary Intervention (RIVER-PCI), a randomized trial in patients with chronic angina pectoris who had incomplete revascularization following percutaneous coronary intervention. At baseline, patients answered how much they agreed with the phrase, "I am optimistic about my future and returning to a normal lifestyle." We evaluated the association between baseline optimism and time to ischemia-driven hospitalization or revascularization using a Cox model, and the association between baseline optimism and change in frequency of angina pectoris using a mixed measures model. Of 2,389 patients, 782 (33.2%) were very optimistic ("strongly agree"), 1,000 (42.4%) were optimistic ("agree"), 451 (19.1%) were neutral ("undecided"), and 123 (5.2%) were not optimistic ("disagree" or "strongly disagree"). Very optimistic patients had a lower prevalence of co-morbidities and less severe angina at baseline than less optimistic patients. The rate of ischemia-driven revascularization or hospitalization was higher in neutral and not optimistic patients compared with very optimistic patients; this finding persisted after adjustment for co-morbidities and baseline angina frequency (hazard ratio 1.42, 95% confidence interval 1.14 to 1.77 for neutral vs very optimistic; hazard ratio 1.38, 95% confidence interval 0.98 to 1.94 for not optimistic vs very optimistic). Neutral and not optimistic patients also had less improvement in angina than very optimistic patients. In conclusion, in patients with angina, those with more self-reported optimism had better health status outcomes. Whether structured interventions targeting optimism improve outcomes in these patients warrants further study.

Previously we have shown that a functional nonsynonymous single nucleotide polymorphism (SNP), rs6318 on the HTR2C gene located on the X-chromosome, is associated with hypothalamic–pituitary–adrenal axis response to a laboratory stress recall task. The present paper reports a validation of the cortisol response to stress in a second, independent sample. The study population consisted of 60 adult participants (73.3% males). Consistent with our prior findings, compared to Cys23 G allele carriers, persons homozygous for the Ser23C allele had a significantly greater average cortisol response (p = 0.007) and area under the curve (p = 0.021) over the course of an emotional stress recall protocol. Also parallel to our prior report, the change in cortisol from baseline to the average during the stress protocol was roughly twice as large among Ser23C homozygotes than among persons with Cys23 G. These findings validate our initial observation of association between rs6318 and cortisol response to an acute stressor, and extend the results to include females.

Background Although emotional stress is associated with ischemic heart disease (IHD) and related clinical events, sex-specific differences in the psychobiological response to mental stress have not been clearly identified. Objectives We aimed to study the differential psychological and cardiovascular responses to mental stress between male and female patients with stable IHD. Methods Patients with stable IHD enrolled in the REMIT (Responses of Mental Stress–Induced Myocardial Ischemia to Escitalopram) study underwent psychometric assessments, transthoracic echocardiography, and platelet aggregation studies at baseline and after 3 mental stress tasks. Mental stress–induced myocardial ischemia (MSIMI) was defined as the development or worsening of regional wall motion abnormality, reduction of left ventricular ejection fraction (LVEF) ≥8% by transthoracic echocardiography, and/or ischemic ST-segment change on electrocardiogram during 1 or more of the 3 mental stress tasks. Results In the 310 participants with known IHD (18% women, 82% men), most baseline characteristics were similar between women and men (including heart rate, blood pressure, and LVEF), although women were more likely to be nonwhite, living alone (p Conclusions In this exploratory analysis, we identified clear, measurable, and differential responses to mental stress in women and men. Further studies should test the association of sex differences in cardiovascular and platelet reactivity in response to mental stress and long-term outcomes. (Responses of Myocardial Ischemia to Escitalopram Treatment [REMIT]; NCT00574847 )

Mental stress induced left ventricular dysfunction (LVD) has been associated with a greater risk of adverse events in coronary heart disease (CHD) patients independent of conventional risk indicators. The underlying biochemical mechanisms of this cardiovascular condition are poorly understood. Our objective was to use metabolomics technology to identify biochemical changes that co-occur with mental stress-induced LVD in patients with clinically stable CHD. Participants were adult CHD patients who were recruited for mental stress-induced myocardial ischemia screening. For this study, we randomly selected 30 patients representing the extremes of the mental stress-induced left ventricular ejection fraction (LVEF) change distribution; 15 who showed LVD (i.e. LVEF reduction ≥5) and 15 who showed a normal left ventricular response (NLVR; i.e. a LVEF increase of ≥5) to three mental stressors. An electrochemistry based metabolomics platform was used to profile pre- and post-stress serum samples yielding data for 22 known compounds, primarily within the tyrosine, tryptophan, purine and methionine pathways. There were significant stress-induced changes in several compounds. A comparison between the NLVR and LVD groups showed significant effects for kynurenine (p = .036, N-acetylserotonin (p = .054), uric acid (p = .015), tyrosine (p = .019) and a trend for methionine (p = .065); the NLVR group showed a significantly greater stress-induced reduction in all of those compounds compared to the LVD group. Many of these biochemicals have been implicated in other stress-related phenomena and are plausible candidates for mechanisms underlying LVD in response to mental stress.

Previous research has shown an association between hostility and fasting glucose in African American women. Central nervous system serotonin activity is implicated both in metabolic processes and in hostility related traits.The purpose of this study is to determine whether central nervous system serotonin influences the association between hostility and fasting glucose in African American women.The study consisted of 119 healthy volunteers (36 African American women, 27 White women, 21 White males, and 35 African American males, mean age 34 ± 8.5 years). Serotonin related compounds were measured in cerebrospinal fluid. Hostility was measured by the Cook-Medley Hostility Scale.Hostility was associated with fasting glucose and central nervous system serotonin related compounds in African American women only. Controlling for the serotonin related compounds significantly reduced the association of hostility to glucose.The positive correlation between hostility and fasting glucose in African American women can partly be explained by central nervous system serotonin function.

The present study used harmonized data from eight studies (N = 28,891) to examine the association between socioeconomic status (SES) and resting systolic blood pressure (SBP). The study replicates and extends our prior work on this topic by examining potential moderation of this association by race and gender. We also examined the extent to which body mass index (BMI), waist circumference (WC), and smoking might explain the association between SES and SBP. Data were available from six race/gender groups: 9200 Black women; 2337 Black men; 7248 White women; 6519 White men; 2950 Hispanic women; and 637 Hispanic men. Multivariable regression models showed that greater annual household income was associated with lower SBP in all groups except Hispanic men. The magnitude and form of this negative association differed across groups, with White women showing the strongest linear negative association. Among Black men and Hispanic women, the association was curvilinear: relatively flat among lower income levels, but then negative among higher income ranges. Education also was independently, negatively related to SBP, though evidence was weaker for race and gender differences in the strength of the association. Higher BMI and WC were associated with higher SBP, and current smoking with lower SBP. Inclusion of these risk factors resulted in only a modest change in the magnitude of the SBP and SES relation, accounting on average about 0.4 mmHg of the effect of income and 0.2 mmHg of the effect of education—effects unlikely to be clinically significant. Further understanding of mechanisms underlying the association between SBP and SES may improve risk stratification in clinical settings and potentially inform interventions aimed at reductions in social disparities in health., Highlights • Harmonized data (n = 28,291) examined association between blood pressure and socioeconomic status. • Replication and extension of prior work by examining potential moderation of this association by race and gender. • Further understanding of this association inform interventions aimed at reductions in social disparities in health.

Clergy suffer from high rates of obesity, chronic disease, and depression, and simultaneously underestimate the toll these take on their daily functioning. Health interventions are needed for clergy and may be tailored to their occupational context and theological beliefs. Few studies have sought to improve clergy health. No prior studies have utilized a randomized design. Spirited Life is a randomized, multiple baseline study that offered enrollment to nearly all United Methodist Church clergy in North Carolina in fall 2010. A total of 1114 clergy (response rate = 64%) enrolled. Using a multiple baseline design, we randomized participants to three cohorts. Each cohort began the health intervention in one of three consecutive years. The third cohort served as a randomized waitlist control cohort, allowing comparisons between the first and third cohorts. The two-year Spirited Life intervention consists of: 1) a theological underpinning for health stewardship based on incarnation, grace, and response and delivered during workshops; 2) the stress management program Williams LifeSkills; 3) Naturally Slim, an online weight loss program; 4) phone contact with a Wellness Advocate; and 5) $500 small grants for health goals. Metabolic syndrome is the primary endpoint. Stress and depressive severity are secondary endpoints. We measured each construct before, twice during, and at the end of the two-year intervention. Study outcomes, to be published after follow-up data are gathered, will provide evidence of the effectiveness of the combined intervention components of Spirited Life. If successful, the intervention may be considered for use with other clergy and faith populations.

TOMM40 SNP rs157580 has been associated with triglyceride levels in genome-wide association studies (GWAS). Chronic caregiving stress moderates the association between triglyceride levels and a nearby SNP rs439401 that is associated with triglyceride levels in GWAS. Here, we report data from two independent Caucasian samples (242 U.S. women and men; 466 Danish men) testing the hypothesis that chronic family stress also moderates the association between rs157580 and triglyceride levels. The interaction of rs157580 and family stress in predicting triglyceride levels was statistically significant in the U.S. sample (p = 0.004) and marginally significant (p = 0.075) in the Danish sample. The G allele of rs157580 was associated with increased triglyceride levels among family stressed cases in both samples compared with A/A cases, but not among controls. Chronic family stress moderates the association of rs157580 variants with triglyceride levels and should be taken into account for disease risk assessment and potential intervention.

ObjectivesThe goal of this study was to evaluate the prevalence and clinical characteristics of mental stress–induced myocardial ischemia.BackgroundMental stress–induced myocardial ischemia is prevalent and a risk factor for poor prognosis in patients with coronary heart disease, but past studies mainly studied patients with exercise-induced myocardial ischemia.MethodsEligible patients with clinically stable coronary heart disease, regardless of exercise stress testing status, underwent a battery of 3 mental stress tests followed by a treadmill test. Stress-induced ischemia, assessed by echocardiography and electrocardiography, was defined as: 1) development or worsening of regional wall motion abnormality; 2) left ventricular ejection fraction reduction ≥8%; and/or 3) horizontal or downsloping ST-segment depression ≥1 mm in 2 or more leads lasting for ≥3 consecutive beats during at least 1 mental test or during the exercise test.ResultsMental stress–induced ischemia occurred in 43.45%, whereas exercise-induced ischemia occurred in 33.79% (p = 0.002) of the study population (N = 310). Women (odds ratio [OR]: 1.88), patients who were not married (OR: 1.99), and patients who lived alone (OR: 2.24) were more likely to have mental stress–induced ischemia (all p < 0.05). Multivariate analysis showed that compared with married men or men living with someone, unmarried men (OR: 2.57) and married women (OR: 3.18), or living alone (male OR: 2.25 and female OR: 2.72, respectively) had higher risk for mental stress–induced ischemia (all p < 0.05).ConclusionsMental stress–induced ischemia is more common than exercise-induced ischemia in patients with clinically stable coronary heart disease. Women, unmarried men, and individuals living alone are at higher risk for mental stress–induced ischemia. (Responses of Myocardial Ischemia to Escitalopram Treatment [REMIT]; NCT00574847)

The chronic stress of caregiving has been associated with increased risk for cognitive decline and dementia. One theoretical model suggests that a group of risk factors known as the metabolic syndrome MET_SYN (e.g., hypertension, poor glucose regulation, central obesity, and high triglyceride levels) that have demonstrated associations with both stress and cognitive decline, may mediate the association between caregiver stress and cognitive decline. It is also possible that caregiving may moderate the association between MET_SYN and cognitive decline. The present study examined these two potential models. The study sample consisted of 53 caregivers for a relative with dementia and 24 participants who did not have caregiving responsibilities at baseline. We examined associations among caregiving history (yes/no), self-reported decline in cognitive function (the AD8) at follow-up, and a MET_SYN factor comprised of increased systolic blood pressure (SBP), glycosylated hemoglobin concentration (HbA1c), waist circumference, and triglyceride levels at baseline when caregiving was assessed. MET_SYN was associated with AD8 (p = 0.010). Caregiving history was not directly associated with AD8 ratings, however, caregiving did moderate the association between MET_SYN and AD8 (p = 0.043) assessed 8 years later. In caregivers MET_SYN scores reflecting higher risk were associated with scores on the AD8 indicting decline, whereas, in controls MET_SYN was unrelated to AD8 assessment. Thus, it can be concluded that caregiver stress may increase the association between metabolic risk factors and decline in cognitive functioning up to 8 years later.

Background Based on prior research finding the 5HTTLPR L allele associated with increased cardiovascular reactivity to laboratory stressors and increased risk of myocardial infarction, we hypothesized that the 5HTTLPR L allele will be associated with increased blood pressure (BP) and increased hypertension prevalence in 2 large nationally representative samples in the United States and Singapore. Methods Logistic regression and linear models tested associations between triallelic (L′S′, based on rs25531) 5HTTLPR genotypes and hypertension severity and mean systolic and diastolic blood pressure (SBP and DBP) collected during the Wave IV survey of the National Longitudinal Study of Adolescent to Adult Health (Add Health, N = 11,815) in 2008–09 and during 2004–07 in 4196 Singaporeans. Results In US Whites, L′ allele carriers had higher SBP (0.9 mm Hg, 95% CI = 0.26-1.56) and greater odds (OR = 1.23, 95% CI = 1.10-1.38) of more severe hypertension than those with S′S′ genotypes. In African Americans, L′ carriers had lower mean SBP (−1.27 mm Hg, 95% CI = −2.53 to −0.01) and lower odds (OR = 0.78, 95% CI = 0.65-0.94) of more severe hypertension than those with the S′S′ genotype. In African Americans, those with L′L′ genotypes had lower DBP (−1.13 mm Hg, 95% CI = −2.09 to −0.16) than S′ carriers. In Native Americans, L′ carriers had lower SBP (−6.05 mm Hg, 95% CI = −9.59 to −2.51) and lower odds of hypertension (OR = 0.34, 95% CI = 0.13-0.89) than those with the S′S′ genotype. In Asian/Pacific Islanders those carrying the L′ allele had lower DBP (−1.77 mm Hg, 95% CI = −3.16 to −0.38) and lower odds of hypertension (OR = 0.68, 95% CI = 0.48-0.96) than those with S′S′. In the Singapore sample S′ carriers had higher SBP (3.02 mm Hg, 95% CI = 0.54-5.51) and DBP (1.90 mm Hg, 95% CI = 0.49-3.31) than those with the L′L′ genotype. Conclusions These findings suggest that Whites carrying the L′ allele, African Americans and Native Americans with the S′S′ genotype, and Asians carrying the S′ allele will be found to be at higher risk of developing cardiovascular disease and may benefit from preventive measures.

Background The rs6265 (Val66Met) single-nucleotide polymorphism in the BDNF gene has been related to a number of endophenotypes that have in turn been shown to confer risk for atherosclerotic cardiovascular disease (CVD). To date, however, very few studies have examined the association of the Val66Met single-nucleotide polymorphism with CVD clinical outcomes. Methods In a cohort of 5,510 Caucasian patients enrolled in the CATHeterization GENetics (CATHGEN) study at Duke University Hospital between 2001 and 2011, we determined the severity of coronary artery disease (CAD) and CVD event incidence through up to 11.8 years of follow-up. We examined the association of Val66Met genotype with time-to-death or myocardial infarction, adjusting for age, sex, CAD risk variables, and CAD severity measures. Results The Val/Val genotype was associated with a higher risk than Met carriers for clinical CVD events ( P = .034, hazard ratio 1.12, 95% CI 1.01-1.24). In addition, compared with Met carriers, individuals with the Val/Val genotype had a greater odds of having more diseased vessels (odds ratio 1.17, 95% CI 1.06-1.30, P = .002), and lower left ventricular ejection fraction (β = −0.72, 95% CI, −1.42 to −0.02, P = .044). Conclusions The Val/Val genotype was associated with greater severity of CAD and incidence of CVD-related clinical events in a patient sample. If these findings are confirmed in further research, intervention studies in clinical groups with the Val/Val genotype could be undertaken to prevent disease and improve prognosis.

Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism has been associated with cortisol responses to stress with gender differences reported, although the findings are not entirely consistent. To evaluate the role of Val66Met genotype and gender on cortisol responses to stress, we conducted a 45-min mental stress protocol including four tasks and four rest periods. Blood cortisol was collected for assay immediately before and after each task and rest period. A significant two-way interaction of Val66Met genotype × gender (P = 0.022) was observed on the total area under the curve (AUC), a total cortisol response over time, such that the Val/Val genotype was associated with a larger cortisol response to stress as compared to the Met group in women but not in men. Further contrast analyses between the Val/Val and Met group for each stress task showed a similar increased cortisol pattern among women Val/Val genotype but not among men. The present findings indicate the gender differences in the effect of Val66Met genotype on the cortisol responses to stress protocol, and extend the evidence for the importance of gender and the role of Val66Met in the modulation of stress reactivity and subsequent depression prevalence. Further studies and the underlying mechanism need to be investigated, which may provide an insight for prevention, intervention, and treatment strategies that target those at high risk.

Depressive symptoms have been associated with myocardial ischemia induced by mental (MSIMI) and exercise (ESIMI) stress in clinically stable ischemic heart disease (IHD) patients, but the association between positive emotions and inducible ischemia is less well characterized. The objective of this study was to examine the associations between ratings of well-being and stress-induced ischemia.Subjects were adult patients with documented IHD underwent mental and exercise stress testing for the Responses of Myocardial Ischemia to Escitalopram Treatment (REMIT) trial. The General Well-Being Schedule (GWBS), with higher scores reflecting greater subjective well-being, and the Center for Epidemiologic Studies Depression Scale (CES-D) were obtained from the REMIT participants. Echocardiography was used to measure ischemic responses to mental stress and Bruce protocol treadmill exercise testing. Data were analyzed using logistic regression adjusting for age, sex, resting left-ventricular ejection fraction (LVEF), and resting wall motion score index, as well as health-related behaviors.GWBS scores were obtained for 210 individuals, with MSIMI present in 92 (43.8%) and ESIMI present in 64 (30.5%). There was a significant inverse correlation between GWBS-PE (Positive Emotion subscale) scores and probability of ESIMI (OR=0.55 (95%CI 0.36-0.83), p=0.005). This association persisted after additional control for CESD subscales measuring negative and positive emotions and for variables reflecting health-related behaviors. A similar inverse correlation between GWBS-PE and MSIMI was observed, but did not reach statistical significance (OR=0.81 (95%CI 0.54-1.20), p=0.28).This is, to our knowledge, the first study demonstrating that greater levels of self-reported positive emotions are associated with a lower likelihood of ESIMI among patients with known IHD. Our results highlight the important interface functions of the central nervous and cardiovascular systems and underscore areas for future investigation.

Here we examine the effects of both self-reported and independent observer-reported environmental risk indices, the serotonin transporter gene promoter (5HTTLPR) polymorphism, and their interaction on self-esteem. This trait was assessed during early and mid adolescence (mean age = 14 and 16.5, respectively) and young adulthood (mean age = 21.8) in a prospective cohort of 1214 unrelated participants in the Longitudinal Study of Adolescent Health (Add Health). Using structural equation modeling we identified a gene–environment (G × E) interaction using observer-report but not self-report measures of environmental stress exposure during adolescence: 5HTTLPR genotype and observer-reports of home and neighborhood quality (HNQ) during adolescence interacted to predict self-esteem levels in young adulthood (p < .004). Carriers of the s allele who lived in poor HNQ conditions during adolescence reported lower self-esteem in young adulthood than those with a good HNQ during adolescence. In contrast, among individuals with the l/l genotype, adolescent HNQ did not predict adulthood self-esteem. Genes may moderate the effect of adolescent environmental conditions on adulthood self-esteem.

The Williams LifeSkills® (WLS) anger and stress management workshop provides training in strategies to cope with stressful situations and build supportive relationships. The purpose of this study was to determine the impact of school-based Williams LifeSkills training on anger, anxiety, and blood pressure in adolescents. One hundred fifty-nine adolescents (mean age ± SD = 15.7 ± 1.4 years) were randomized to WLS (n = 86) or control (CTL, n = 73) groups. The WLS group engaged in twelve 50-min WLS training sessions conducted by teachers at school. Anger-in and anxiety scores decreased and anger-control scores increased in the WLS group across the six-month follow-up period compared to the CTL group (group x visit, ps

Background Mental stress–induced myocardial ischemia (MSIMI) is common in patients with clinically stable coronary heart disease (CHD) and is associated with poor outcomes. Depression is a risk factor of MSIMI. The REMIT trial investigates whether selective serotonin reuptake inhibitor (SSRI) treatment can improve MSIMI. The rationale and outline of the study are described. Method In this single-center randomized clinical trial, adult patients with clinically stable CHD are recruited for baseline mental and exercise stress testing assessed by echocardiography. In addition, psychometric questionnaires are administered, and blood samples are collected for platelet activity analysis. Patients who demonstrate MSIMI, defined by new abnormal wall motion, ejection fraction reduction ≥8%, and/or development of ischemic ST change in electrocardiogram during mental stress testing, are randomized at a 1:1 ratio to escitalopram or placebo for 6 weeks. Approximately 120 patients with MSIMI are enrolled in the trial. The stress testing, platelet activity assessment, and psychometric questionnaires are repeated at the end of the 6-week intervention. The hypothesis of the study is that SSRI treatment improves MSIMI via mood regulation and modification of platelet activity. Conclusion The REMIT study examines the effect of SSRI on MSIMI in vulnerable patients with CHD and probes some potential underlying mechanisms.

In the National Longitudinal Study of Adolescent Health, a US longitudinal study of >15 000 young adults, we examined the extent to which socioeconomic status is linked to systolic blood pressure (SBP) and whether biobehavioral risk factors mediate the association. More than 62% of the participants had SBP >120 mm Hg and 12% had SBP >140 mm Hg. More than 66% were classified as at least overweight (body mass index >25 kg/m 2 ), with >36% meeting criteria for at least class I obesity (body mass index >30 kg/m 2 ). Multivariate models showed that higher household income and being married were independently associated with lower SBP. Higher body mass index, greater waist circumference, smoking, and higher alcohol intake were each independently associated with higher SBP. Meditational analyses suggested that higher education level was associated with lower SBP by way of lower body mass, smaller waist circumference, and lower resting heart rate. When these indirect effects were accounted for, education was not significantly associated with SBP. In contrast, household income remained associated with SBP even with control for all of the covariates. Results reinforce current public health concerns about rates of obesity and high blood pressure among young adults and suggest that disparities in education level and household income may play an important role in the observed decrements in health. Identifying modifiable mechanisms that link socioeconomic status to SBP using data from a large representative sample may improve risk stratification and guide the development of effective interventions.

OBJECTIVES To replicate a prior main effect of the serotonin transporter gene promoter (5HTTLPR) genotype on cardiovascular reactivity (CVR) and explore caregiver stress as a potential moderator of 5HTTLPR effects on CVR. On the basis of prior findings, we hypothesized that the more transcriptionally active allele variants would be associated with increased CVR. METHODS Expression of the serotonin transporter is affected by the genotype of the 5HTTLPR (S-short and L-long forms) as well as the genotype of the SNP rs25531 within this region. Based on the combined genotypes for these polymorphisms, we designated each allele as a Hi or Lo expressing allele according to expression levels-resulting in HiHi, HiLo, and LoLo groups. We examined the relationship between 5HTTLPR genotype and CVR in 164 caregivers and 158 noncaregivers. Main effects of 5HTTLPR on baseline adjusted blood pressure (systolic and diastolic blood pressures) and heart rate (HR) reactivity were examined, along with moderation by caregiving. RESULTS The 5HTTLPR × Caregiver Stress interaction moderated both systolic blood pressure (p < .02) and HR (p < .02) reactivity. In controls, the Hi activity allelic variants were associated with greater systolic blood pressure and HR reactivity as compared with the Lo activity variants. In caregivers, 5HTTLPR genotype was not associated with CVR. CONCLUSIONS Replication in this study's control group of our prior finding that 5HTTLPR alleles associated with Hi activity are associated with increased CVR to an emotion recall stressor strengthens the case that this association is real and could be partially responsible for the increased cardiovascular disease observed in persons carrying the 5HTTLPR L allele.

Objective We evaluated the effect of perceived discrimination, optimism, and their interaction on health care utilization among African American adults with sickle cell disease(SCD). Methods Measures of optimism and perceived discrimination were obtained in 49 African American SCD patients. Multiple regression analyses controlling for sex and age tested effects of optimism and perceived discrimination on the number of emergency department visits (ED) and number and duration of hospitalizations over the past year. Results A perceived discrimination-optimism interaction was associated with number of emergency departments visits (b = .29, p = .052), number of hospitalizations (b = .36, p = .019), and duration of hospitalizations (b = .30, p = .045) such that those with high perceived discrimination/high optimism had the greatest health care utilization. Conclusions African American SCD patients with high perceived discrimination/high optimism had greater health care utilization than patients who reported either low perceived discrimination or low optimism. This study suggests that patient personality and coping styles should be considered when evaluating the effects of stress on SCD-related outcomes.