Psychological Distress and the Risk of Adverse Cardiovascular Outcomes in Patients With Coronary Heart Disease.

BACKGROUND: Psychological distress is a recognized risk factor in patients with coronary heart disease (CHD), but its clinical significance is unclear. OBJECTIVES: The purpose of this study was to determine if an index of psychological distress is independently associated with adverse outcomes and significantly contributes to risk prediction. METHODS: Pooled analysis of 2 prospective cohort studies of patients with stable CHD (N = 891). A psychological distress score was constructed using measures of depression, anxiety, anger, perceived stress, and post-traumatic stress disorder, measured at baseline. The study endpoint included cardiovascular death or first or recurrent nonfatal myocardial infarction or hospitalization for heart failure at 5.9 years. RESULTS: In both cohorts, first and recurrent events occurred more often among those in the highest tertile of distress score than those in the lowest tertile. After combining the 2 cohorts, compared with the lowest tertile, the hazards ratio for having a distress score in the highest tertile was 2.27 (95% CI: 1.69-3.06), and for the middle tertile, it was 1.52 (95% CI: 1.10-2.08). Adjustment for demographics and clinical risk factors only slightly weakened the associations. When the distress score was added to a traditional clinical risk model, C-statistic, net reclassification index, and integrative discrimination index all significantly improved. CONCLUSIONS: Among patients with CHD, a composite measure of psychological distress was significantly associated with an increased risk of adverse events and significantly improved risk prediction.

Association between depression and epigenetic age acceleration: A co-twin control study.

INTRODUCTION: Prior studies have shown inconsistent findings of an association between depression and epigenetic aging. DNA methylation (DNAm) age acceleration can measure biological aging. We adopted a robust co-twin control study design to examine whether depression is associated with DNAm age acceleration after accounting for the potential confounding influences of genetics and family environment. METHODS: We analyzed data on a sub-cohort of the Vietnam Era Twin Registry. A total of 291 twins participated at baseline and 177 at follow-up visit after a mean of 11.7 years, with 111 participants having DNA samples for both time points. Depression was measured using the Beck Depression Inventory II (BDI-II). Six measures of DNAm age acceleration were computed at each time point, including Horvath's DNAm age acceleration (HorvathAA), intrinsic epigenetic age acceleration (IEAA), Hannum's DNAm age acceleration (HannumAA), extrinsic epigenetic age acceleration (EEAA), GrimAge acceleration (GrimAA), and PhenoAge acceleration (PhenoAA). Mixed-effects modeling was used to assess the within-pair association between depression and DNAm age acceleration. RESULTS: At baseline, a 10-unit higher BDI-II total score was associated with HannumAA (0.73 years, 95% confidence interval [CI] 0.13-1.33, p = .019) and EEAA (0.94 years, 95% CI 0.22-1.66, p = .012). At follow-up, 10-unit higher BDI-II score was associated with PhenoAA (1.32 years, 95% CI 0.18-2.47, p = .027). CONCLUSION: We identified that depression is associated with higher levels of DNAm age acceleration. Further investigation is warranted to better understand the underlying mechanisms for the potential causal relationship between depression and accelerated aging.

Application of Noninvasive Vagal Nerve Stimulation to Stress-Related Psychiatric Disorders.

BACKGROUND: Vagal Nerve Stimulation (VNS) has been shown to be efficacious for the treatment of depression, but to date, VNS devices have required surgical implantation, which has limited widespread implementation. METHODS: New noninvasive VNS (nVNS) devices have been developed which allow external stimulation of the vagus nerve, and their effects on physiology in patients with stress-related psychiatric disorders can be measured with brain imaging, blood biomarkers, and wearable sensing devices. Advantages in terms of cost and convenience may lead to more widespread implementation in psychiatry, as well as facilitate research of the physiology of the vagus nerve in humans. nVNS has effects on autonomic tone, cardiovascular function, inflammatory responses, and central brain areas involved in modulation of emotion, all of which make it particularly applicable to patients with stress-related psychiatric disorders, including posttraumatic stress disorder (PTSD) and depression, since dysregulation of these circuits and systems underlies the symptomatology of these disorders. RESULTS: This paper reviewed the physiology of the vagus nerve and its relevance to modulating the stress response in the context of application of nVNS to stress-related psychiatric disorders. CONCLUSIONS: nVNS has a favorable effect on stress physiology that is measurable using brain imaging, blood biomarkers of inflammation, and wearable sensing devices, and shows promise in the prevention and treatment of stress-related psychiatric disorders.

A Pilot Study of the Effects of Mindfulness-Based Stress Reduction on Post-traumatic Stress Disorder Symptoms and Brain Response to Traumatic Reminders of Combat in Operation Enduring Freedom/Operation Iraqi Freedom Combat Veterans with Post-traumatic Stress Disorder.

OBJECTIVE: Brain imaging studies in patients with post-traumatic stress disorder (PTSD) have implicated a circuitry of brain regions including the medial prefrontal cortex, amygdala, hippocampus, parietal cortex, and insula. Pharmacological treatment studies have shown a reversal of medial prefrontal deficits in response to traumatic reminders. Mindfulness-based stress reduction (MBSR) is a promising non-pharmacologic approach to the treatment of anxiety and pain disorders. The purpose of this study was to assess the effects of MBSR on PTSD symptoms and brain response to traumatic reminders measured with positron-emission tomography (PET) in Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) combat veterans with PTSD. We hypothesized that MBSR would show increased prefrontal response to stress and improved PTSD symptoms in veterans with PTSD. METHOD: Twenty-six OEF/OIF combat veterans with PTSD who had recently returned from a combat zone were block randomized to receive eight sessions of MBSR or present-centered group therapy (PCGT). PTSD patients underwent assessment of PTSD symptoms with the Clinician-Administered PTSD Scale (CAPS), mindfulness with the Five Factor Mindfulness Questionnaire (FFMQ) and brain imaging using PET in conjunction with exposure to neutral and Iraq combat-related slides and sound before and after treatment. Nine patients in the MBSR group and 8 in the PCGT group completed all study procedures. RESULTS: Post-traumatic stress disorder patients treated with MBSR (but not PCGT) had an improvement in PTSD symptoms measured with the CAPS that persisted for 6 months after treatment. MBSR also resulted in an increase in mindfulness measured with the FFMQ. MBSR-treated patients had increased anterior cingulate and inferior parietal lobule and decreased insula and precuneus function in response to traumatic reminders compared to the PCGT group. CONCLUSION: This study shows that MBSR is a safe and effective treatment for PTSD. Furthermore, MBSR treatment is associated with changes in brain regions that have been implicated in PTSD and are involved in extinction of fear responses to traumatic memories as well as regulation of the stress response.

Association of vitamin D status with mental stress-induced myocardial ischemia in patients with coronary artery disease.

BACKGROUND: Mental stress-induced (MSIMI) or physical stress-induced (PSIMI) myocardial ischemia portends a worse prognosis in patients with coronary artery disease (CAD). Vitamin D insufficiency is associated with adverse cardiovascular outcomes, but its relationship to myocardial ischemia remains unclear. We hypothesized that vitamin D insufficiency will be associated with a higher prevalence of myocardial ischemia in patients with CAD. METHODS: In 255 patients with stable CAD, myocardial perfusion imaging was performed to assess ischemia in response to mental and physical stress protocols. Vitamin D insufficiency was defined as serum 25-hydroxyvitamin D [25(OH)D] levels below 30 ng/ml, collected on the day of stress testing. RESULTS: Mean (standard deviation) 25(OH)D level was 30.8 (12.8) ng/ml, and 139 (55%) patients had vitamin D insufficiency. MSIMI occurred in 30 (12%) patients and PSIMI in 67 (27%). Individuals with MSIMI had significantly lower levels of 25(OH)D as compared with those without MSIMI (24.0 [8.6] versus 31.7 [12.9], p = .002). The prevalence of MSIMI was higher in those with as compared with those without vitamin D insufficiency (17% versus 6%, p = .009). Moreover, low 25(OH)D levels remained independently associated with MSIMI after adjusting for potential confounders. Conversely, 25(OH)D levels were similar between those with or without PSIMI (29.8 [13.0] versus 31.4 [12.7], p = .37), as was the prevalence of PSIMI in those with or without vitamin D insufficiency (29% versus 24%, p = .42). CONCLUSIONS: Vitamin D insufficiency is associated with a higher prevalence of MSIMI but not PSIMI among stable patients with CAD. Whether this association serves as a potential mechanism linking low vitamin D status to adverse cardiovascular outcomes warrants further investigation.

Sex differences in mental stress-induced myocardial ischemia in young survivors of an acute myocardial infarction.

OBJECTIVES: Emotional stress may disproportionally affect young women with ischemic heart disease. We sought to examine whether mental stress-induced myocardial ischemia (MSIMI), but not exercise-induced ischemia, is more common in young women with previous myocardial infarction (MI) than in men. METHODS: We studied 98 post-MI patients (49 women and 49 men) aged 38 to 60 years. Women and men were matched for age, MI type, and months since MI. Patients underwent technetium-99m sestamibi perfusion imaging at rest, after mental stress, and after exercise/pharmacological stress. Perfusion defect scores were obtained with observer-independent software. A summed difference score (SDS), the difference between stress and rest scores, was used to quantify ischemia under both stress conditions. RESULTS: Women 50 years or younger, but not older women, showed a more adverse psychosocial profile than did age-matched men but did not differ for conventional risk factors and tended to have less angiographic coronary artery disease. Compared with age-matched men, women 50 years or younger exhibited a higher SDS with mental stress (3.1 versus 1.5, p = .029) and had twice the rate of MSIMI (SDS ≥ 3; 52% versus 25%), whereas ischemia with physical stress did not differ (36% versus 25%). In older patients, there were no sex differences in MSIMI. The higher prevalence of MSIMI in young women persisted when adjusting for sociodemographic and life-style factors, coronary artery disease severity, and depression. CONCLUSIONS: MSIMI post-MI is more common in women 50 years or younger compared with age-matched men. These sex differences are not observed in post-MI patients who are older than 50 years.

Is heart rate variability related to memory performance in middle-aged men?

OBJECTIVE: Heart rate variability (HRV), a measure of autonomic function, has been associated with cognitive function, but studies are conflicting. Previous studies have also not controlled for familial and genetic influences. METHODS: We performed power spectral analysis on 24-hour ambulatory ECGs in 416 middle-aged male twins from the Vietnam Era Twin Registry. Memory and learning were measured by verbal and visual Selective Reminding Tests (SRTs). Mixed-effect regression models were used to calculate associations between and within twin pairs, while adjusting for covariates. RESULTS: The mean age (standard deviation) was 55 (2.9) years. A statistically significant positive association was found between measures of HRV and verbal, but not visual, SRT scores. The most statistically significant unadjusted association was found between very low frequency HRV and verbal total recall SRT, such that each logarithm of increase in very low frequency was associated with an increased verbal SRT score of 4.85 points (p = .002). The association persisted despite the adjustment for demographic and cardiovascular risk factors, and after accounting for familial and genetic factors by comparing twins within pairs. A significant interaction was found between posttraumatic stress disorder (PTSD) and HRV, such that total power and ultra low frequency were associated with SRT in twins (n = 362) without PTSD, but not in those with PTSD. CONCLUSIONS: Lower frequency spectra of HRV are associated with verbal, but not visual, learning and memory, particularly in subjects without PTSD. This association may indicate that autonomic nervous system dysregulation plays a role in cognitive decline.

Validation and test-retest reliability of Early Trauma Inventory in Spanish postpartum women.

The aims were to study the validity and test-retest reliability of the Early Trauma Inventory-Self Report (ETI-SR) and its short-form (ETI-SF), which retrospectively assess different childhood trauma, in a sample of Spanish postpartum women. A total of 227 healthy postpartum women completed the ETI-SR and ETI-SF. The longitudinal, expert, all data procedure was used as the external criterion for the assessment of childhood trauma. The ETI-SR and ETI-SF were also administered to a sample of 102 postpartum depressive women (DSM-IV) and the results were compared with those of the healthy postpartum sample. The area under the curve values of the ETI-SR and ETI-SF were 0.77 (95% confidence interval [CI], 0.71-0.84) and 0.78 (95% CI, 0.72-0.85), the internal consistencies of the 2 scales were 0.79 and 0.72, and the intraclass correlation coefficients were 0.92 (95% CI, 0.80-0.97) and 0.91 (95% CI, 0.78-0.96), all respectively. The ETI-SR and ETI-SF had higher test-retest reliability on all subscales. The ETI-SR and ETI-SF are shown to be valid and reliable instruments for assessing childhood trauma in postpartum women.

Pleiotropy of C-reactive protein gene polymorphisms with C-reactive protein levels and heart rate variability in healthy male twins.

Reduced heart rate variability (HRV) and increased C-reactive protein (CRP) levels are both predictors of coronary artery disease and correlate with each other. We examined whether these 2 phenotypes share a common genetic substrate and investigated the relations of the CRP gene polymorphisms with both CRP levels and HRV indexes. We examined 236 male twins free of symptomatic coronary artery disease, with a mean age +/- SD of 54 +/- 2.9 years. The plasma CRP levels were measured and the frequency domain measures of HRV were assessed using a 24-hour electrocardiographic recording, including ultra-low-, very-low-, low-, and high-frequency power. Three single-nucleotide polymorphisms in the CRP gene were genotyped. Generalized estimating equations were used to examine the association between CRP and HRV, as well as the genotype-phenotype association. Bivariate structural equation modeling was performed to estimate the genetic and environmental correlations between CRP and HRV and the explanatory effect of CRP gene polymorphisms on the CRP-HRV association. Both CRP (h(2) = 0.76) and HRV indexes (h(2) = 0.56 to 0.64) showed high heritability. Greater CRP levels were significantly associated with lower HRV. A robust genetic correlation was found between CRP and ultra-low-frequency power (r(G) = -0.3, p = 0.001). One CRP single nucleotide polymorphism (rs1205) was significantly associated with both CRP (p = 0.003) and ultra-low-frequency power (p = 0.005) and explained 11% of the genetic covariance between them. In conclusion, reduced HRV correlates significantly with increased CRP plasma levels and this correlation is due, in large part, to common genetic influences. A polymorphism in the CRP gene contributes to both CRP levels and HRV.

Effects of a cognitive stress challenge on myocardial perfusion and plasma cortisol in coronary heart disease patients with depression.

Although it is well established that coronary heart disease (CHD) patients with depression exhibit increased mortality compared with equally ill cardiac patients without depression, the mechanisms mediating this effect remain obscure. Depression is characterized by vulnerability to stress and heightened stress responsiveness, and stress can theoretically act through several biological pathways to contribute to excess mortality from CHD. Mechanisms connecting stress, depression and cardiovascular mortality have not been previously explored in detail. The purpose of this study was to assess the effects of stress and depression on myocardial perfusion and plasma cortisol concentrations in CHD patients. Patients with CHD with and without depression (n = 28) underwent single photon emission computed tomography imaging of myocardial perfusion at rest and during a stressful cognitive challenge. Severity of ischaemia was measured by summing perfusion defect scores across myocardial segments and subtracting out rest from stress scores. Plasma cortisol concentrations were measured at baseline and in response to the stressful challenge. There were no differences in stress-induced myocardial ischaemia or plasma cortisol response to stress between CHD patients with and without depression. Depressed CHD patients with a history of psychological trauma (n = 5) had an increase in stress-induced ischaemia scores [7; standard deviation (SD) = 5] compared with CHD patients with depression without a history of psychological trauma (2 SD = 2) and CHD patients without depression or psychological trauma (1; SD = 2) (F = 8.51; degree of freedom = 2,23; p = 0.007). Eighty per cent of CHD/depression trauma-exposed subjects had stress-induced ischaemia as opposed to 38 per cent of CHD/depression subjects without trauma exposure and 23 per cent of subjects with CHD without depression or trauma. Self-reported nervousness during the cognitive stressor was correlated with stress-induced ischaemia. These preliminary findings suggest that depression with a history of prior exposure to traumatic stress is associated with increased risk for stress-induced cardiovascular ischaemia.