Posttraumatic Stress Disorder and Impaired Autonomic Modulation in Male Twins

BACKGROUND: Posttraumatic stress disorder (PTSD) has been linked to increased morbidity. An inflexibility of the autonomic nervous system may be the underlying mechanism. We aimed to assess whether PTSD and combat trauma exposure are associated with lower heart rate variability (HRV), a measure of autonomic function and a predictor of death. METHODS: We measured HRV by power spectral analysis on 24-hour ambulatory ECG in 459 middle-aged veteran male twins. Combat trauma was assessed with the combat exposure scale, and current and remitted PTSD with the Structured Clinical Interview for Psychiatry Disorders. Mixed-effects regression models were used to test associations of PTSD and HRV between and within twin pairs. RESULTS: Of all twins, 211 had combat exposure, 31 had current PTSD, and 43 had remitted PTSD. Current PTSD was inversely associated with very-low frequency (VLF) and low frequency (LF) HRV both in individual twins and within 20 pairs discordant for current PTSD. Twins with current PTSD had a 49% lower LF HRV than their brothers without PTSD (p<0.001). Remitted PTSD was not associated with HRV. Results were robust to adjustment for depression and other risk factors. Combat exposure was inversely associated with most HRV frequencies, but this association mostly diminished after adjustment for current PTSD. CONCLUSION: In middle-aged veteran men, combat exposure and current PTSD are associated with measures of autonomic inflexibility previously shown to have prognostic significance. The negative health impact of combat exposure on autonomic function is mediated largely through PTSD and may reverse with remission of PTSD

Association between Posttraumatic Stress Disorder and Inflammation: A Twin Study

The association of posttraumatic stress disorder (PTSD) with cardiovascular disease risk may be mediated by inflammation. Our objective was to examine the association between PTSD and measures of inflammation and to determine whether these associations are due to shared familial or genetic factors. We measured lifetime history of PTSD using the Structured Clinical Interview for DSM-IV in 238 male middle-aged military veteran twin pairs (476 individuals), selected from the Vietnam Era Twins Registry, who were free of cardiovascular disease at baseline. We assessed inflammation using levels of high-sensitivity C-reactive protein (hsCRP), interleukin 6 (IL-6), fibrinogen, white blood cells, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1 (ICAM-1). Geometric mean levels and percent differences by PTSD were obtained from mixed-model linear regression analyses with adjustment for potential confounders. Within-pair analysis was conducted to adjust for shared family environment and genetics (monozygotic pairs). Overall, 12.4% of participants had a lifetime history of PTSD. Adjusted mean levels of hsCRP and ICAM-1 were significantly higher among those with vs. without PTSD [hsCRP: 1.75 vs. 1.31 mg/l (33% difference); ICAM-1: 319 vs. 293 ng/ml (9% difference)]. Adjustment for depression rendered the association of PTSD with hsCRP non-statistically significant. For IL-6, no consistent association was seen. Within-pair analysis produced associations that were similar in direction for all three markers but lesser in magnitude for hsCRP and IL-6. There was no evidence of interaction by zygosity. Elevated hsCRP and ICAM-1 are associated with PTSD, and these associations may be confounded by shared non-genetic, antecedent familial and environmental factors

Association Between Ideal Cardiovascular Health and Carotid Intima-Media Thickness: A Twin Study

Background The American Heart Association (AHA) recently developed the Cardiovascular Health Index (CVHI), a health metric consisting of 7 modifiable risk factors. The relationship of the CVHI with preclinical markers, such as carotid intima-media thickness (CIMT) has not been assessed. Methods We examined 490 male monozygotic and dizygotic twins without overt cardiovascular disease. CIMT was measured using B-mode ultrasonography. Each of the 7 CVHI components (blood pressure, fasting glucose, total cholesterol, body mass index, physical activity, healthy diet, and smoking) was given a point score of 0, 1, or 2 to represent poor, intermediate, or ideal health, respectively. A CVHI summation score was computed (range 0 to 14) and categorized as inadequate (0 to 4), average (5 to 9), or optimum (10 to 14) cardiovascular health. Mixed-model regression was used to examine the association of the CVHI with CIMT. Results The mean age of the twins was 55.4 years, and 61% were monozygotic. The mean CIMT was 0.75 (±0.11) mm and the mean CVHI score was 7.7 (±2.1). There was an inverse correlation between CVHI and CIMT (Spearman r=−0.22, P\u3c0.01). For every 5-unit increase in overall CVHI score (indicating better cardiovascular health category), CIMT decreased by 0.045 mm (P\u3c0.001) after adjusting for demographic variables and other confounders. Within monozygotic twin pairs, a 5-unit increment in CVHI score was associated with a 0.05 mm lower CIMT (P\u3c0.001). Conclusions The CVHI is independently associated with CIMT and the association is not confounded by shared genetic and other familial factors

Posttraumatic Stress Disorder and Incidence of Coronary Heart Disease: A Twin Study

OBJECTIVES: To determine whether posttraumatic stress disorder (PTSD) is associated with coronary heart disease (CHD) using a prospective twin study design and objective measures of CHD. BACKGROUND: It has long been hypothesized that PTSD increases the risk of CHD but empirical evidence using objective measures is limited. METHODS: We conducted a prospective study of middle-aged male twins from the Vietnam Era Twin Registry. Among twin pairs without self-reported CHD at baseline, we selected pairs discordant for a lifetime history of PTSD, pairs discordant for a lifetime history of major depression, and pairs without either condition. All underwent a clinic visit after a median follow-up of 13 years. Outcomes included clinical events (myocardial infarction, other hospitalizations for CHD and coronary revascularization) and quantitative measures of myocardial perfusion by [N13] positron emission tomography, including a stress total severity score (STSS) and coronary flow reserve (CFR). RESULTS: A total of 562 twins (281 pairs) were included with mean age of 42.6 yrs at baseline. The incidence of CHD was more than double in twins with PTSD (22.6%) than those without PTSD (8.9%; p<0.001). The association remained robust after adjusting for lifestyle factors, other CHD risk factors and major depression (OR=2.2, 95% confidence interval, 1.2-4.1). STSS was significantly higher (+ 95%, p=0.001) and CFR lower (−0.21, p=0.02) in twins with PTSD than those without, denoting worse myocardial perfusion. Associations were only mildly attenuated within 117 twin pairs discordant for PTSD. CONCLUSIONS: Among Vietnam era veterans, PTSD is a risk factor for CHD

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

Non-Image-Forming Light Driven Functions Are Preserved in a Mouse Model of Autosomal Dominant Optic Atrophy

Autosomal dominant optic atrophy (ADOA) is a slowly progressive optic neuropathy that has been associated with mutations of the OPA1 gene. In patients, the disease primarily affects the retinal ganglion cells (RGCs) and causes optic nerve atrophy and visual loss. A subset of RGCs are intrinsically photosensitive, express the photopigment melanopsin and drive non-image-forming (NIF) visual functions including light driven circadian and sleep behaviours and the pupil light reflex. Given the RGC pathology in ADOA, disruption of NIF functions might be predicted. Interestingly in ADOA patients the pupil light reflex was preserved, although NIF behavioural outputs were not examined. The B6; C3-Opa1Q285STOP mouse model of ADOA displays optic nerve abnormalities, RGC dendropathy and functional visual disruption. We performed a comprehensive assessment of light driven NIF functions in this mouse model using wheel running activity monitoring, videotracking and pupillometry. Opa1 mutant mice entrained their activity rhythm to the external light/dark cycle, suppressed their activity in response to acute light exposure at night, generated circadian phase shift responses to 480 nm and 525 nm pulses, demonstrated immobility-defined sleep induction following exposure to a brief light pulse at night and exhibited an intensity dependent pupil light reflex. There were no significant differences in any parameter tested relative to wildtype littermate controls. Furthermore, there was no significant difference in the number of melanopsin-expressing RGCs, cell morphology or melanopsin transcript levels between genotypes. Taken together, these findings suggest the preservation of NIF functions in Opa1 mutants. The results provide support to growing evidence that the melanopsin-expressing RGCs are protected in mitochondrial optic neuropathies

Stress-Induced Reinstatement of Drug Seeking: 20 Years of Progress

In human addicts, drug relapse and craving are often provoked by stress. Since 1995, this clinical scenario has been studied using a rat model of stress-induced reinstatement of drug seeking. Here, we first discuss the generality of stress-induced reinstatement to different drugs of abuse, different stressors, and different behavioral procedures. We also discuss neuropharmacological mechanisms, and brain areas and circuits controlling stress-induced reinstatement of drug seeking. We conclude by discussing results from translational human laboratory studies and clinical trials that were inspired by results from rat studies on stress-induced reinstatement. Our main conclusions are (1) The phenomenon of stress-induced reinstatement, first shown with an intermittent footshock stressor in rats trained to self-administer heroin, generalizes to other abused drugs, including cocaine, methamphetamine, nicotine, and alcohol, and is also observed in the conditioned place preference model in rats and mice. This phenomenon, however, is stressor specific and not all stressors induce reinstatement of drug seeking. (2) Neuropharmacological studies indicate the involvement of corticotropin-releasing factor (CRF), noradrenaline, dopamine, glutamate, kappa/dynorphin, and several other peptide and neurotransmitter systems in stress-induced reinstatement. Neuropharmacology and circuitry studies indicate the involvement of CRF and noradrenaline transmission in bed nucleus of stria terminalis and central amygdala, and dopamine, CRF, kappa/dynorphin, and glutamate transmission in other components of the mesocorticolimbic dopamine system (ventral tegmental area, medial prefrontal cortex, orbitofrontal cortex, and nucleus accumbens). (3) Translational human laboratory studies and a recent clinical trial study show the efficacy of alpha-2 adrenoceptor agonists in decreasing stress-induced drug craving and stress-induced initial heroin lapse

Thyroid function tests in the reference range and fracture: individual participant analysis of prospective cohorts.

Context Hyperthyroidism is associated with increased fracture risk, but it is not clear if lower TSH and higher free thyroxine (FT4) in euthyroid individuals are associated with fracture risk. Objective To evaluate the association of TSH and FT4 with incident fractures in euthyroid individuals. Design Individual participant data analysis. Setting Thirteen prospective cohort studies with baseline examinations between 1981 and 2002. Participants Adults with baseline TSH 0.45-4.49 mIU/L. Main Outcome Measures Primary outcome was incident hip fracture. Secondary outcomes were any, non-vertebral, and vertebral fractures. Results were presented as hazard ratios (HR) with 95% confidence interval (CI) adjusted for age and sex. For clinical relevance, we studied TSH according to five categories: 0.45-0.99mIU/L; 1.00-1.49mIU/L; 1.50-2.49mIU/L; 2.50-3.49mIU/L; 3.50-4.49mIU/L (reference). FT4 was assessed as study-specific standard deviation increase, because assays varied between cohorts. Results During 659,059 person-years, 2,565/56,835 participants had hip fracture (4.5%; 12 studies with data on hip fracture). The pooled adjusted HR (95% CI) for hip fracture was 1.25 (1.05-1.49) for TSH 0.45-0.99mIU/L, 1.19 (1.01-1.41) for TSH 1.00-1.49mIU/L, 1.09 (0.93-1.28) for TSH 1.50-2.49mIU/L, and 1.12 (0.94-1.33) for TSH 2.50-3.49mIU/L (P for trend = 0.004). Hip fracture was also associated with FT4 (HR [95%CI] 1.22 [1.11-1.35] per one standard deviation increase in FT4). FT4 only was associated with any and non-vertebral fracture. Results remained similar in sensitivity analyses. Conclusions Among euthyroid adults, lower TSH and higher FT4 are associated with an increased risk of hip fracture. These findings may help refine the definition of optimal ranges of thyroid function tests