Posttraumatic Stress Disorder and Obstructive Sleep Apnea in Twins.

Importance: Obstructive sleep apnea (OSA) is a common condition in older adult (aged >65 years) populations, but more mechanistic research is needed to individualize treatments. Previous evidence has suggested an association between OSA and posttraumatic stress disorder (PTSD) but is limited by possible selection bias. High-quality research on this association with a careful evaluation of possible confounders may yield important mechanistic insight into both conditions and improve treatment efforts. Objective: To investigate the association of current PTSD symptoms and PTSD diagnosis with OSA. Design, Setting, and Participants: This cross-sectional study of twin pairs discordant for PTSD, which allows for adjustment for familial factors, was conducted using in-laboratory polysomnography from March 20, 2017, to June 3, 2019. The study sample comprised male veteran twins recruited from the Vietnam Era Twin Registry. The data analysis was performed between June 11, 2022, and January 30, 2023. Exposure: Symptoms of PTSD in twins who served in the Vietnam War. Diagnosis of PTSD was a secondary exposure. Main Outcomes and Measures: Obstructive sleep apnea was assessed using the apnea-hypopnea index (AHI) (≥4% oxygen saturation criterion as measured by events per hour) with overnight polysomnography. Symptoms of PTSD were assessed using the PTSD Checklist (PCL) and structured clinical interview for PTSD diagnosis. Results: A total of 181 male twins (mean [SD] age, 68.4 [2.0] years) including 66 pairs discordant for PTSD symptoms and 15 pairs discordant for a current PTSD diagnosis were evaluated. In models examining the PCL and OSA within pairs and adjusted for body mass index (BMI) and other sociodemographic, cardiovascular, and psychiatric risk factors (including depression), each 15-point increase in PCL was associated with a 4.6 (95% CI, 0.1-9.1) events-per-hour higher AHI. Current PTSD diagnosis was associated with an adjusted 10.5 (95% CI, 5.7-15.3) events-per-hour higher AHI per sleep-hour. Comparable standardized estimates of the association of PTSD symptoms and BMI with AHI per SD increase (1.9 events per hour; 95% CI, 0.5-3.3 events per hour) were found. Conclusions and Relevance: This cross-sectional study found an association between PTSD and sleep-disordered breathing. The findings have important public health implications and may also enhance understanding of the many factors that potentially affect OSA pathophysiology.

Transcutaneous vagal nerve stimulation modulates stress-induced plasma ghrelin levels: A double-blind, randomized, sham-controlled trial.

BACKGROUND: Transcutaneous cervical vagus nerve stimulation (tcVNS) has emerged as a potential treatment strategy for patients with stress-related psychiatric disorders. Ghrelin is a hormone that has been postulated to be a biomarker of stress. While the mechanisms of action of tcVNS are unclear, we hypothesized that tcVNS reduces the levels of ghrelin in response to stress. METHODS: Using a randomized double-blind approach, we studied the effects of tcVNS on ghrelin levels in individuals with a history of exposure to traumatic stress. Participants received either sham (n = 29) or active tcVNS (n = 26) after exposure to acute personalized traumatic script stress and mental stress challenges (public speech, mental arithmetic) over a three day period. RESULTS: There were no significant differences in the levels of ghrelin between the tcVNS and sham stimulation groups at either baseline or in the absence of trauma scripts. However, tcVNS in conjunction with personalized traumatic scripts resulted in lower ghrelin levels compared to the sham stimulation group (265.2 ± 143.6 pg/ml vs 478.7 ± 349.2 pg/ml, P = 0.01). Additionally, after completing the public speaking and mental arithmetic tests, ghrelin levels were found to be lower in the group receiving tcVNS compared to the sham group (293.3 ± 102.4 pg/ml vs 540.3 ± 203.9 pg/ml, P = 0.009). LIMITATIONS: Timing of ghrelin measurements, and stimulation of only left vagus nerve. CONCLUSION: tcVNS decreases ghrelin levels in response to various stressful stimuli. These findings are consistent with a growing literature that tcVNS modulates hormonal and autonomic responses to stress.

Association between PTSD and Impedance Cardiogram-based contractility metrics during trauma recall: A controlled twin study.

Post-traumatic stress disorder (PTSD) is an independent risk factor for incident heart failure, but the underlying cardiac mechanisms remained elusive. Impedance cardiography (ICG), especially when measured during stress, can help understand the underlying psychophysiological pathways linking PTSD with heart failure. We investigated the association between PTSD and ICG-based contractility metrics (pre-ejection period (PEP) and Heather index (HI)) using a controlled twin study design with a laboratory-based traumatic reminder stressor. PTSD status was assessed using structured clinical interviews. We acquired synchronized electrocardiograms and ICG data while playing personalized-trauma scripts. Using linear mixed-effects models, we examined twins as individuals and within PTSD-discordant pairs. We studied 137 male veterans (48 pairs, 41 unpaired singles) from Vietnam War Era with a mean (standard deviation) age of 68.5(2.5) years. HI during trauma stress was lower in the PTSD vs. non-PTSD individuals (7.2 vs. 9.3 [ohm/s2 ], p = .003). PEP reactivity (trauma minus neutral) was also more negative in PTSD vs. non-PTSD individuals (-7.4 vs. -2.0 [ms], p = .009). The HI and PEP associations with PTSD persisted for adjusted models during trauma and reactivity, respectively. For within-pair analysis of eight PTSD-discordant twin pairs (out of 48 pairs), PTSD was associated with lower HI in neutral, trauma, and reactivity, whereas no association was found between PTSD and PEP. PTSD was associated with reduced HI and PEP, especially with trauma recall stress. This combination of increased sympathetic activation and decreased cardiac contractility combined may be concerning for increased heart failure risk after recurrent trauma re-experiencing in PTSD.

Association of Autonomic Activation with traumatic reminder challenges in posttraumatic stress disorder: A co-twin control study.

Post-traumatic stress disorder (PTSD) has been associated with cardiovascular disease (CVD), but the mechanisms remain unclear. Autonomic dysfunction, associated with higher CVD risk, may be triggered by acute PTSD symptoms. We hypothesized that a laboratory-based trauma reminder challenge, which induces acute PTSD symptoms, provokes autonomic dysfunction in a cohort of veteran twins. We investigated PTSD-associated real-time physiologic changes with a simulation of traumatic experiences in which the twins listened to audio recordings of a one-minute neutral script followed by a one-minute trauma script. We examined two heart rate variability metrics: deceleration capacity (DC) and logarithmic low frequency (log-LF) power from beat-to-beat intervals extracted from ambulatory electrocardiograms. We assessed longitudinal PTSD status with a structured clinical interview and the severity with the PTSD Symptoms Scale. We used linear mixed-effects models to examine twin dyads and account for cardiovascular and behavioral risk factors. We examined 238 male Veteran twins (age 68 ± 3 years old, 4% black). PTSD status and acute PTSD symptom severity were not associated with DC or log-LF measured during the neutral session, but were significantly associated with lower DC and log-LF during the traumatic script listening session. Long-standing PTSD was associated with a 0.38 (95% confidence interval, -0.83,-0.08) and 0.79 (-1.30,-0.29) standardized unit lower DC and log-LF, respectively, compared to no history of PTSD. Traumatic reminders in patients with PTSD lead to real-time autonomic dysregulation and suggest a potential causal mechanism for increased CVD risk, based on the well-known relationships between autonomic dysfunction and CVD mortality.

Gender Disparities Between Neighborhood Social Vulnerability and Psychological Distress Among Patients with Heart Disease.

Background: Psychological stress disorders are twice as prevalent in women with ischemic heart disease compared to men. The disproportionate psychological health experience of these women is not well understood. The objective of this study was to examine whether neighborhood social factors are associated with disparities in psychological health by gender. Materials and Methods: We studied 286 patients with heart disease recruited from Emory-based hospitals in the Myocardial Infarction and Mental Stress 2 Study (n = 286). A global measure of psychological distress was calculated by taking an average of ranks across symptom scales for depression, post-traumatic stress disorder, anxiety, anger, and perceived stress. The social vulnerability index (SVI) was developed by the Centers for Disease Control and Prevention and was used to rank patients' census tracks on 14 social factors. Beta coefficients for mean ranks in psychological distress scores were estimated per 10-unit increase in SVI percentile ranking using multilevel regression models. Results: The mean age of the sample was 51 years, 49% were women, and 66% African American. After adjusting for demographics, cardiovascular risk factors, and antidepressant use, each 10-unit increase in SVI percentile ranking was associated with 4.65 (95% CI: 0.61-8.69; p = 0.02) unit increase in mean scores for psychological distress among women only (SVI-by-gender-interaction = 0.01). These associations were driven by the SVI themes of lower socioeconomic status and poorer access to housing and transportation. Conclusion: Neighborhood social vulnerability may be a psychosocial stressor that potentiates women's susceptibility to adverse psychological and cardiovascular health.

Data-driven approach for automatic detection of aortic valve opening: B point detection from impedance cardiogram.

Pre-ejection period (PEP), an indicator of sympathetic nervous system activity, is useful in psychophysiology and cardiovascular studies. Accurate PEP measurement is challenging and relies on robust identification of the timing of aortic valve opening, marked as the B point on impedance cardiogram (ICG) signals. The ICG sensitivity to noise and its waveform's morphological variability makes automated B point detection difficult, requiring inefficient and cumbersome expert visual annotation. In this article, we propose a machine learning-based automated algorithm to detect the aortic valve opening for PEP measurement, which is robust against noise and ICG morphological variations. We analyzed over 60 hr of synchronized ECG and ICG records from 189 subjects. A total of 3657 averaged beats were formed using our recently developed ICG noise removal algorithm. Features such as the averaged ICG waveform, its first and second derivatives, as well as high-level morphological and critical hemodynamic parameters were extracted and fed into the regression algorithms to estimate the B point location. The morphological features were extracted from our proposed "variable" physiologically valid search-window related to diverse B point shapes. A subject-wise nested cross-validation procedure was performed for parameter tuning and model assessment. After examining multiple regression models, Adaboost was selected, which demonstrated superior performance and higher robustness to five state-of-the-art algorithms that were evaluated in terms of low mean absolute error of 3.5 ms, low median absolute error of 0.0 ms, high correlation with experts' estimates (Pearson coefficient = 0.9), and low standard deviation of errors of 9.2 ms. For reproducibility, an open-source toolbox is provided.

The temporal relationships between sleep disturbance and autonomic dysregulation: A co-twin control study.

INTRODUCTION: Sleep disturbance is associated with autonomic dysregulation, but the temporal directionality of this relationship remains uncertain. The objective of this study was to evaluate the temporal relationships between objectively measured sleep disturbance and daytime or nighttime autonomic dysregulation in a co-twin control study. METHODS: A total of 68 members (34 pairs) of the Vietnam Era Twin Registry were studied. Twins underwent 7-day in-home actigraphy to derive objective measures of sleep disturbance. Autonomic function indexed by heart rate variability (HRV) was obtained using 7-day ECG monitoring with a wearable patch. Multivariable vector autoregressive models with Granger causality tests were used to examine the temporal directionality of the association between daytime and nighttime HRV and sleep metrics, within twin pairs, using 7-day collected ECG data. RESULTS: Twins were all male, mostly white (96%), with mean (SD) age of 69 (2) years. Higher daytime HRV across multiple domains was bidirectionally associated with longer total sleep time and lower wake after sleep onset; these temporal dynamics were extended to a window of 48 h. In contrast, there was no association between nighttime HRV and sleep measures in subsequent nights, or between sleep measures from previous nights and subsequent nighttime HRV. CONCLUSIONS: Daytime, but not nighttime, autonomic function indexed by HRV has bidirectional associations with several sleep dimensions. Dysfunctions in autonomic regulation during wakefulness can lead to subsequent shorter sleep duration and worse sleep continuity, and vice versa, and their influence on each other may extend beyond 24 h.

Validation of a new impedance cardiography analysis algorithm for clinical classification of stress states.

Pre-ejection period (PEP) is an index of sympathetic nervous system activity that can be computed from electrocardiogram (ECG) and impedance cardiogram (ICG) signals, but sensitive to speech/motion artifact. We sought to validate an ICG noise removal method, three-stage ensemble-average algorithm (TEA), in data acquired from a clinical trial comparing active versus sham non-invasive vagal nerve stimulation (tcVNS) after standardized speech stress. We first compared TEA's performance versus the standard conventional ensemble-average algorithm (CEA) approach to classify noisy ICG segments. We then analyzed ECG and ICG data to measure PEP and compared group-level differences in stress states with each approach. We evaluated 45 individuals, of whom 23 had post-traumatic stress disorder (PTSD). We found that the TEA approach identified artifact-corrupted beats with intraclass correlation coefficient > 0.99 compared to expert adjudication. TEA also resulted in higher group-level differences in PEP between stress states than CEA. PEP values were lower in the speech stress (vs. baseline rest) group using both techniques, but the differences were greater using TEA (12.1 ms) than CEA (8.0 ms). PEP differences in groups divided by PTSD status and tcVNS (active vs. sham) were also greater when using the TEA versus CEA method, although the magnitude of the differences was lower. In conclusion, TEA helps to accurately identify noisy ICG beats during speaking stress, and this increased accuracy improves sensitivity to group-level differences in stress states compared to CEA, suggesting greater clinical utility.

Early Life Trauma Is Associated With Increased Microvolt T-Wave Alternans During Mental Stress Challenge: A Substudy of Mental Stress Ischemia: Prognosis and Genetic Influences.

Background Early life trauma has been associated with increased cardiovascular risk, but the arrhythmic implications are unclear. We hypothesized that in patients with coronary artery disease, early life trauma predicts increased arrhythmic risk during mental stress, measured by elevated microvolt T-wave alternans (TWA), a measure of repolarization heterogeneity and sudden cardiac death risk. Methods and Results In a cohort with stable coronary artery disease (NCT04123197), we examined early life trauma with the Early Trauma Inventory Self Report-Short Form. Participants underwent a laboratory-based mental stress speech task with Holter monitoring, as well as a structured psychiatric interview. We measured TWA during rest, mental stress, and recovery with ambulatory electrocardiographic monitoring. We adjusted for sociodemographic factors, cardiac history, psychiatric comorbidity, and hemodynamic stress reactivity with multivariable linear regression models. We examined 320 participants with noise- and arrhythmia-free ECGs. The mean (SD) age was 63.8 (8.7) years, 27% were women, and 27% reported significant childhood trauma (Early Trauma Inventory Self Report-Short Form ≥10). High childhood trauma was associated with a multivariable-adjusted 17% increase in TWA (P=0.04) during stress, and each unit increase in the Early Trauma Inventory Self Report-Short Form total score was associated with a 1.7% higher stress TWA (P=0.02). The largest effect sizes were found with the emotional trauma subtype. Conclusions In a cohort with stable coronary artery disease, early life trauma, and in particular emotional trauma, is associated with increased TWA, a marker of increased arrhythmic risk, during mental stress. This association suggests that early trauma exposures may affect long-term sudden cardiac death risk during emotional triggers, although more studies are warranted.

Early life stress and autonomic response to acute mental stress in individuals with coronary heart disease.

Early life stress (ELS) has been associated with an increased risk of cardiovascular disease. We examined whether ELS was associated with autonomic function and stress reactivity among individuals with coronary heart disease (CHD). We included patients with stable CHD from two parallel studies, the Mental Stress Ischemia Prognosis Study (MIPS) and the Myocardial Infarction and Mental Stress Study 2 (MIMS2), and assessed ELS using the Early Trauma Inventory-Self-Report-Short Form. Participants underwent a laboratory-based mental stress task while undergoing ambulatory electrocardiographic monitoring. We used multivariate linear regression models to estimate the associations between ELS and heart rate variability (HRV; low frequency [LF], high frequency [HF], and LF and HF [LH] ratio). The analytic sample included 405 MIPS and 284 MIMS2 participants. Most participants endorsed at least one experience of ELS (92.2%). Although we did not observe associations between ELS and HRV outcomes in the overall sample, ELS was associated with lower LH ratio HRV during recovery in the posttraumatic stress disorder (PTSD) subgroup, ELS x PTSD interaction, p = .041. In the MIMS2 subgroup, ELS was associated with lower resting period LF HRV, B ̂ $ \widehat{B} $  = -0.16 ln ms2 ; 95% CI [-0.31, -0.02]. Exposure to physical trauma was associated with decreased HF HRV overall reactivity only among participants with high to moderate depressive symptoms, B ̂ $ \widehat{B} $  = -0.52 ln ms2 vs. B ̂ $ \widehat{B} $  = 0.01 ln ms2 , p = .013. Overall, heterogeneous associations between ELS and HRV emerged, suggesting the need for additional research regarding longer-term ambulatory HRV.

Association of Depressive Symptoms with Sleep Disturbance: A Co-twin Control Study.

BACKGROUND: Few studies have comprehensively evaluated the association of depression with sleep disturbance using a controlled twin study design. PURPOSE: To cross-sectionally evaluate the association of depression with both objective and subjective sleep disturbance. METHODS: We studied 246 members of the Vietnam Era Twin Registry. We measured depressive symptoms using the Beck Depression Inventory-II (BDI) and assessed major depression using structured clinical interviews. Twins underwent one-night polysomnography and 7-day actigraphy to derive measures of objective sleep and completed the Pittsburgh Sleep Quality Index for subjective sleep. Multivariable mixed-effects models were used to examine the association. RESULTS: Twins were all male, mostly white (97%), with a mean (SD) age of 68 (2). The mean (SD) BDI was 5.9 (6.3), and 49 (20%) met the criteria for major depression. For polysomnography, each 5-unit higher BDI, within-pair, was significantly associated with 19.7 min longer rapid eye movement (REM) sleep latency, and 1.1% shorter REM sleep after multivariable adjustment. BDI was not associated with sleep architecture or sleep-disordered breathing. For actigraphy, a higher BDI, within-pair, was significantly associated with lower sleep efficiency, more fragmentation and higher variability in sleep duration. BDI was associated with almost all dimensions of self-reported sleep disturbance. Results did not differ by zygosity, and remained consistent using major depression instead of BDI and were independent of the presence of comorbid posttraumatic stress disorder and antidepressant use. CONCLUSIONS: Depression is associated with REM sleep disruption in lab and sleep fragmentation and sleep variability at home, but not with sleep architecture or sleep-disordered breathing.

Association Between Posttraumatic Stress Disorder and Epigenetic Age Acceleration in a Sample of Twins.

OBJECTIVE: Posttraumatic stress disorder (PTSD) has been related to accelerated biological aging processes, but objective evidence for this association is limited. DNA methylation (DNAm) age acceleration is a novel measure of biological aging that may help clarify if PTSD is related to biological aging processes. We aim to examine whether PTSD is associated with biological aging using a comprehensive set of DNAm age acceleration markers and to what extent the unshared environment contributes to the association. METHODS: Using a cross-sectional co-twin control study design, we investigated the association of the clinical diagnosis and symptom severity of PTSD with six measurements of DNAm age acceleration based on epigenome-wide data derived from peripheral blood lymphocytes of 296 male twins from the Vietnam Era Twin Registry. RESULTS: Twins with current PTSD had significantly advanced DNAm age acceleration compared with twins without PTSD for five of six measures of DNAm age acceleration. Across almost all measures of DNAm age acceleration, twins with current PTSD were "epigenetically older" than their twin brothers without PTSD: estimated differences ranged between 1.6 (95% confidence interval = 0.0-3.1) and 2.7 (95% confidence interval = 0.5-4.8) biological age year-equivalents. A higher Clinician-Administered PTSD Scale score was also associated with a higher within-pair DNAm age acceleration. Results remained consistent after adjustment for behavioral and cardiovascular risk factors. CONCLUSIONS: PTSD is associated with epigenetic age acceleration, primarily through unshared environmental mechanisms as opposed to genetic or familial factors. These results suggest that PTSD is related to systemic processes relevant to biological aging.

Posttraumatic Stress Disorder, Myocardial Perfusion, and Myocardial Blood Flow: A Longitudinal Twin Study.

BACKGROUND: The link between posttraumatic stress disorder (PTSD) and ischemic heart disease remains elusive owing to a shortage of longitudinal studies with a clinical diagnosis of PTSD and objective measures of cardiac compromise. METHODS: We performed positron emission tomography in 275 twins who participated in two examinations approximately 12 years apart. At both visits, we obtained a clinical diagnosis of PTSD, which was classified as long-standing (both visit 1 and visit 2), late onset (only visit 2), and no PTSD (no PTSD at both visits). With positron emission tomography, we assessed myocardial flow reserve (MFR), which, in absence of significant coronary stenoses, indexes coronary microvascular function. We compared positron emission tomography data at visit 2 across the three categories of longitudinally assessed PTSD and examined changes between the two visits. RESULTS: Overall, 80% of the twins had no or minimal obstructive coronary disease. Yet, MFR was depressed in twins with PTSD and was progressively lower across groups with no PTSD (2.13), late-onset PTSD (1.97), and long-standing PTSD (1.93) (p = .01). A low MFR (a ratio <2.0) was present in 40% of the twins without PTSD, in 56% of those with late-onset PTSD, and in 72% of those with long-standing PTSD (p < .001). Associations persisted in multivariable analysis, when examining changes in MFR between visit 1 and visit 2, and within twin pairs. Results were similar by zygosity. CONCLUSIONS: Longitudinally, PTSD is associated with reduced coronary microcirculatory function and greater deterioration over time. The association is especially noted among twins with chronic, long-standing PTSD and is not confounded by shared environmental or genetic factors.

Transcutaneous Cervical Vagus Nerve Stimulation Inhibits the Reciprocal of the Pulse Transit Time's Responses to Traumatic Stress in Posttraumatic Stress Disorder.

Research has shown that transcutaneous cervical vagus nerve stimulation (tcVNS) yields downstream changes in peripheral physiology in individuals afflicted with posttraumatic stress disorder (PTSD). While the cardiovascular effects of tcVNS have been studied broadly in prior work, the specific effects of tcVNS on the reciprocal of the pulse transit time (1/PTT) remain unknown. By quantifying detectable effects, tcVNS can be further evaluated as a counterbalance to sympathetic hyperactivity during distress - specifically, we hypothesized that tcVNS would inhibit 1/PTT responses to traumatic stress. To investigate this, the electrocardiogram (ECG), photoplethysmogram (PPG), and seismocardiogram (SCG), were simultaneously measured from 24 human subjects suffering from PTSD. Implementing state-of-the-art signal quality assessment algorithms, relative changes in the pulse arrival time (PAT) and the pre-ejection period (PEP) were estimated solely from signal segments of sufficient quality. Thereby computing relative changes in 1/PTT, we find that tcVNS results in reduced 1/PTT responses to traumatic stress and the first minute of stimulation, compared to a sham control (corrected p < 0.05). This suggests that tcVNS induces inhibitory effects on blood pressure (BP) and/or vasoconstriction, given the established relationship between 1/PTT and these parameters.Clinical Relevance- Relative changes in 1/PTT are induced by varying vasomotor tone and/or BP - it has therefore piqued considerable interest as a potential surrogate of continuous BP. Studying its responses to tcVNS thus furthers understanding of tcVNS-induced cardiovascular modulation. The positive effects detailed herein suggest a potential role for tcVNS in the long-term management of PTSD.

Transcutaneous Cervical Vagal Nerve Stimulation in Patients with Posttraumatic Stress Disorder (PTSD): A Pilot Study of Effects on PTSD Symptoms and Interleukin-6 Response to Stress.

BACKGROUND: Posttraumatic stress disorder (PTSD) is a highly disabling condition associated with alterations in multiple neurobiological systems, including increases in inflammatory and sympathetic function, responsible for maintenance of symptoms. Treatment options including medications and psychotherapies have limitations. We previously showed that transcutaneous Vagus Nerve Stimulation (tcVNS) blocks inflammatory (interleukin (IL)-6) responses to stress in PTSD. The purpose of this study was to assess the effects of tcVNS on PTSD symptoms and inflammatory responses to stress. METHODS: Twenty patients with PTSD were randomized to double blind active tcVNS (N=9) or sham (N=11) stimulation in conjunction with exposure to personalized traumatic scripts immediately followed by active or sham tcVNS and measurement of IL-6 and other biomarkers of inflammation. Patients then self administered active or sham tcVNS twice daily for three months. PTSD symptoms were measured with the PTSD Checklist (PCL) and the Clinician Administered PTSD Scale (CAPS), clinical improvement with the Clinical Global Index (CGI) and anxiety with the Hamilton Anxiety Scale (Ham-A) at baseline and one-month intervals followed by a repeat of measurement of biomarkers with traumatic scripts. After three months patients self treated with twice daily open label active tcVNS for another three months followed by assessment with the CGI. RESULTS: Traumatic scripts increased IL-6 in PTSD patients, an effect that was blocked by tcVNS (p<.05). Active tcVNS treatment for three months resulted in a 31% greater reduction in PTSD symptoms compared to sham treatment as measured by the PCL (p=0.013) as well as hyperarousal symptoms and somatic anxiety measured with the Ham-A p<0.05). IL-6 increased from baseline in sham but not tcVNS. Open label tcVNS resulted in improvements measured with the CGI compared to the sham treatment period p<0.05). CONCLUSIONS: These preliminary results suggest that tcVNS reduces inflammatory responses to stress, which may in part underlie beneficial effects on PTSD symptoms.

Racial Disparities in Adverse Cardiovascular Outcomes After a Myocardial Infarction in Young or Middle-Aged Patients.

Background Black patients tend to develop coronary artery disease at a younger age than other groups. Previous data on racial disparities in outcomes of myocardial infarction (MI) have been inconsistent and limited to older populations. Our objective was to investigate racial differences in the outcome of MI among young and middle-aged patients and the role played by socioeconomic, psychosocial, and clinical differences. Methods and Results We studied 313 participants (65% non-Hispanic Black) <61 years old hospitalized for confirmed type 1 MI at Emory-affiliated hospitals and followed them for 5 years. We used Cox proportional-hazard models to estimate the association of race with a composite end point of recurrent MI, stroke, heart failure, or cardiovascular death after adjusting for demographic, socioeceonomic status, psychological, and clinical risk factors. The mean age was 50 years, and 50% were women. Compared with non-Black patients, Black patients had lower socioeconomic status and more clinical and psychosocial risk factors but less angiographic coronary artery disease. The 5-year incidence of cardiovascular events was higher in Black (35%) compared to non-Black patients (19%): hazard ratio (HR) 2.1, 95% CI, 1.3 to 3.6. Adjustment for socioeconomic status weakened the association (HR 1.3, 95% CI, 0.8-2.4) more than adjustment for clinical and psychological risk factors. A lower income explained 46% of the race-related disparity in outcome. Conclusions Among young and middle-aged adult survivors of an MI, Black patients have a 2-fold higher risk of adverse outcomes, which is largely driven by upstream socioeconomic factors rather than downstream psychological and clinical risk factors.

Epigenetic Age Acceleration and Cognitive Decline: A Twin Study.

BACKGROUND: Little is known about the role of DNA methylation (DNAm) epigenetic age acceleration in cognitive decline. Using a twin study design, we examined whether DNAm age acceleration is related to cognitive decline measured longitudinally in persons without a clinical diagnosis of dementia. METHODS: We studied 266 paired male twins (133 pairs) with a mean age of 56 years at baseline. Of these, 114 paired twins returned for a follow-up after an average of 11.5 years. We obtained 6 indices of DNAm age acceleration based on epigenome-wide data from peripheral blood lymphocytes. At both baseline and follow-up, we administered a battery of cognitive measures and constructed 2 composite scores, one for executive function and one for memory function. We fitted multivariable mixed regression models to examine the association of DNAm age acceleration markers with cognitive function within pairs. RESULTS: In cross-sectional analyses at baseline, there was no association between DNAm age acceleration and cognitive function scores. In longitudinal analyses, however, comparing twins within pairs, each additional year of age acceleration using the Horvath's method was associated with a 3% decline (95% CI, 1%-5%) in the composite executive function score and a 2.5% decline (95% CI, 0.01%-4.9%) in the memory function score. These results did not attenuate after adjusting for education and other risk factors. CONCLUSIONS: Middle-aged men who had older DNAm age relative to their brothers of the same demographic age showed a faster rate of cognitive decline in the subsequent 11.5 years. These results point to the role of epigenetic modifications in cognitive aging.

Sex differences in the inflammatory response to stress and risk of adverse cardiovascular outcomes among patients with coronary heart disease.

Stress may contribute to progression of coronary heart disease (CHD) through inflammation, especially among women. Thus, we sought to examine whether increased inflammatory response to stress among patients with CHD is associated with a greater risk of cardiovascular events and whether this risk is higher in women. We examined inflammatory biomarkers known to increase with mental stress (speech task), including interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and matrix metallopeptidase-9 (MMP-9) among 562 patients with stable CHD. Inflammatory response, the difference between post-stress and resting values, was examined as a predictor of major adverse cardiovascular events (MACE) using subdistribution hazards models for competing risks adjusting for demographics, cardiovascular risk factors, and medications. MACE was defined as a composite endpoint of cardiovascular death, myocardial infarction, unstable angina with revascularization, and heart failure. All biomarkers were standardized. The mean age was 63 years (range 34-79) and 24% were women. During a median follow-up of 3 years, 71 patients experienced MACE. Overall, there was no significant association between inflammatory response to stress and risk of MACE, but there were sex-based interactions for IL-6 (p = 0.001) and MCP-1 (p = 0.01). The risk of MACE increased 56% (HR: 1.56; 95% CI: 1.21, 2.01; p = 0.001) and 30% (HR: 1.30; 95% 1.09, 1.55; p = 0.004) for each standard deviation increase in IL-6 and MCP-1 response to mental stress for women, respectively, while there was no association among men. Increased inflammation in response to stress is associated with future adverse cardiovascular outcomes among women with CHD.

Relation of High-sensitivity Cardiac Troponin I Elevation With Exercise to Major Adverse Cardiovascular Events in Patients With Coronary Artery Disease.

High sensitive cardiac troponin I (hs-cTnI) increases with inducible myocardial ischemia in patients with coronary artery disease (CAD). We aimed to assess if the change in hs-cTnI levels with exercise stress testing is associated with major adverse cardiac events (MACE). A cohort of 365 (age 62 ± 9 years, 77% men) patients with stable CAD underwent 99mTc sestamibi myocardial perfusion imaging with treadmill testing. Plasma hs-cTnI level was measured at rest and at 45 min after stress. Multivariable Fine & Gray's subdistribution hazards models were used to determine the association between the change in hs-cTnI and MACE, a composite end point of cardiovascular death, myocardial infarction, and unstable angina requiring revascularization. During a median follow-up of 3 years, 39 (11%) patients experienced MACE. After adjustment, for each two-fold increment in hs-cTnI with stress, there was a 2.2 (95% confidence interval 1.3-3.6)-fold increase in the hazard for MACE. Presence of both a high resting hs-cTnI level (>median) and ≥ 20% stress-induced hs-cTnI elevation was associated with the highest incidence of MACE (subdistribution hazards models 4.6, 95% confidence interval 1.6 to 13.0) compared with low levels of both. Risk discrimination statistics significantly improved after addition of resting and change in hs-cTnI levels to a model including traditional risk factors and inducible ischemia (0.67 to 0.71). Conversely, adding inducible ischemia by SPECT did not significantly improve the C-statistic from a model including traditional risk factors, baseline and change in hs-cTnI (0.70 to 0.71). In stable CAD patients, higher resting levels and elevation of hs-cTnI with exercise are predictors of adverse cardiovascular outcomes beyond traditional cardiovascular risk factors and presence of inducible ischemia.

An open-source automated algorithm for removal of noisy beats for accurate impedance cardiogram analysis.

OBJECTIVE: The impedance cardiogram (ICG) is a non-invasive sensing modality for assessing the mechanical aspects of cardiac function, but is sensitive to artifacts from respiration, speaking, motion, and electrode displacement. Electrocardiogram (ECG)-synchronized ensemble averaging of ICG (conventional ensemble averaging method) partially mitigates these disturbances, as artifacts from intra-subject variability (ISVar) of ICG morphology and event latency remain. This paper describes an automated algorithm for removing noisy beats for improved artifact suppression in ensemble-averaged (EA) ICG beats. APPROACH: Synchronized ECG and ICG signals from 144 male subjects at rest in different psychological conditions were recorded. A 'three-stage EA ICG beat' was formed by passing 60-seconds non-overlapping ECG-synchronized ICG signals through three filtering stages. The amplitude filtering stage removed spikes/noisy beats with amplitudes outside of normal physiological ranges. Cross-correlation was applied to remove noisy beats in coarse and fine filtering stages. The accuracy of the algorithm-detected artifacts was measured with expert-identified artifacts. Agreement between the expert and the algorithm was assessed using intraclass correlation coefficients (ICC) and Bland-Altman plots. The ISVar of the cardiac parameters was evaluated to quantify improvement in these estimates provided by the proposed method. MAIN RESULTS: The proposed algorithm yielded an accuracy of 96.3% and high inter-rater reliability (ICC > 0.997). Bland-Altman plots showed consistently accurate results across values. The ISVar of the cardiac parameters derived using the proposed method was significantly lower than those derived via conventional ensemble averaging method (p < 0.0001). Enhancement in resolution of fiducial points and smoothing of higher-order time derivatives of the EA ICG beats were observed. SIGNIFICANCE: The proposed algorithm provides a robust framework for removal of noisy beats and accurate estimation of ICG-based parameters. Importantly, the methodology reduced the ISVar of cardiac parameters. An open-source toolbox has been provided to enable other researchers to readily reproduce and improve upon this work.