Hemodynamic Reactivity to Mental Stress and Cognitive Function in Coronary Artery Disease.

OBJECTIVE: People with coronary artery disease (CAD) are at higher risk of cognitive impairment than those without CAD. Psychological stress is a risk factor for both conditions and assessing the hemodynamic reactivity to mental stress could explain the link between stress and cognitive function. METHODS: Individuals with stable CAD from two prospective cohort studies were included. All individuals underwent acute mental stress testing, as well as conventional stress testing. Cognitive function was assessed both at baseline and at a 2-year follow-up. The rate-pressure product (RPP) was calculated as the mean systolic blood pressure times the mean heart rate at rest. RPP reactivity was defined as the maximum RPP during standardized mental stress test minus the RPP at rest. RESULTS: After multivariable adjustment, every standard deviation decrease in RPP reactivity with mental stress was associated with slower completion of Trail-A and Trail-B in both cohorts (13% and 11% in cohort 1, and 15% and 16% in cohort 2, respectively, p for all <0.01). After a 2-year follow-up period, every standard deviation decrease in RPP reactivity with mental stress was associated with a 8%, and 9% slower completion of Trail-A and Trail-B, respectively (p for all <0.01). There was no significant association between RPP reactivity with conventional stress testing and any of the cognitive tests. CONCLUSION: In the CAD population, a blunted hemodynamic response to mental stress is associated with slower visuomotor processing and worse executive function at baseline and with greater decline in these abilities over time.

Sex Differences in Vascular Response to Mental Stress and Adverse Cardiovascular Events Among Patients With Ischemic Heart Disease.

BACKGROUND: Microvascular measures of vascular dysfunction during acute mental stress may be important determinants of major adverse cardiovascular events (MACE), especially among younger and middle-aged women survivors of an acute myocardial infarction. METHODS: In the MIMS2 study (Myocardial Infarction and Mental Stress 2), individuals who had been hospitalized for a myocardial infarction in the past 8 months were prospectively followed for 5 years. MACE was defined as a composite index of cardiovascular death and first/recurring events for nonfatal myocardial infarction and hospitalizations for heart failure. Reactive hyperemia index and flow-mediated dilation were used to measure microvascular and endothelial function, respectively, before and 30 minutes after a public-speaking mental stress task. Survival models for recurrent events were used to examine the association between vascular response to stress (difference between poststress and resting values) and MACE. Reactive hyperemia index and flow-mediated dilation were standardized in analyses. RESULTS: Of 263 patients (the mean age was 51 years; range, 25-61), 48% were women, and 65% were Black. During a median follow-up of 4.3 years, 64 patients had 141 adverse cardiovascular events (first and repeated). Worse microvascular response to stress (for each SD decrease in the reactive hyperemia index) was associated with 50% greater risk of MACE (hazard ratio, 1.50 [95% CI, 1.05-2.13]; P=0.03) among women only (sex interaction: P=0.03). Worse transient endothelial dysfunction in response to stress (for each SD decrease in flow-mediated dilation) was associated with a 35% greater risk of MACE (hazard ratio, 1.35 [95% CI, 1.07-1.71]; P=0.01), and the association was similar in women and men. CONCLUSIONS: Peripheral microvascular dysfunction with mental stress was associated with adverse events among women but not men. In contrast, endothelial dysfunction was similarly related to MACE among both men and women. These results suggest a female-specific mechanism linking psychological stress to adverse outcomes.

Impedance cardiogram based exploration of cardiac mechanisms in post-traumatic stress disorder during trauma recall.

Post-traumatic stress disorder (PTSD) is an independent risk factor for developing heart failure; however, the underlying cardiac mechanisms are still elusive. This study aims to evaluate the real-time effects of experimentally induced PTSD symptom activation on various cardiac contractility and autonomic measures. We recorded synchronized electrocardiogram and impedance cardiogram from 137 male veterans (17 PTSD, 120 non-PTSD; 48 twin pairs, 41 unpaired singles) during a laboratory-based traumatic reminder stressor. To identify the parameters describing the cardiac mechanisms by which trauma reminders can create stress on the heart, we utilized a feature selection mechanism along with a random forest classifier distinguishing PTSD and non-PTSD. We extracted 99 parameters, including 76 biosignal-based and 23 sociodemographic, medical history, and psychiatric diagnosis features. A subject/twin-wise stratified nested cross-validation procedure was used for parameter tuning and model assessment to identify the important parameters. The identified parameters included biomarkers such as pre-ejection period, acceleration index, velocity index, Heather index, and several physiology-agnostic features. These identified parameters during trauma recall suggested a combination of increased sympathetic nervous system (SNS) activity and deteriorated cardiac contractility that may increase the heart failure risk for PTSD. This indicates that the PTSD symptom activation associates with real-time reductions in several cardiac contractility measures despite SNS activation. This finding may be useful in future cardiac prevention efforts.

Heart-brain axis: Pushing the boundaries of cardiovascular molecular imaging.

Despite decades of research, the heart-brain axis continues to challenge investigators seeking to unravel its complex pathobiology. Strong epidemiologic evidence supports a link by which insult or injury to one of the organs increases the risk of pathology in the other. The putative pathways have important differences between sexes and include alterations in autonomic function, metabolism, inflammation, and neurohormonal mechanisms that participate in crosstalk between the heart and brain and contribute to vascular changes, the development of shared risk factors, and oxidative stress. Recently, given its unique ability to characterize biological processes in multiple tissues simultaneously, molecular imaging has yielded important insights into the interplay of these organ systems under conditions of stress and disease. Yet, additional research is needed to probe further into the mechanisms underlying the heart-brain axis and to evaluate the impact of targeted interventions.

Racial Differences in Mental Stress-Induced Transient Endothelial Dysfunction and Its Association With Cardiovascular Outcomes.

OBJECTIVE: This study aimed to investigate differences in transient endothelial dysfunction (TED) with mental stress in Black and non-Black individuals with coronary heart disease (CHD), and their potential impact on cardiovascular outcomes. METHODS: We examined 812 patients with stable CHD between June 2011 and March 2016 and followed through February 2020 at a university-affiliated hospital network. Flow-mediated vasodilation (FMD) was assessed before and 30 minutes after mental stress. TED was defined as a lower poststress FMD than prestress FMD. We compared prestress FMD, post-stress FMD, and TED between Black and non-Black participants. In both groups, we examined the association of TED with an adjudicated composite end point of cardiovascular death or nonfatal myocardial infarction (first and recurring events) after adjusting for demographic, clinical, and socioeconomic factors. RESULTS: Prestress FMD was lower in Black than non-Black participants (3.7 [2.8] versus 4.9 [3.8], p < .001) and significantly declined with mental stress in both groups. TED occurred more often in Black (76%) than non-Black patients (67%; multivariable-adjusted odds ratio = 1.6, 95% confidence interval = 1.5-1.7). Over a median (interquartile range) follow-up period of 75 (65-82) months, 142 (18%) patients experienced either cardiovascular death or nonfatal myocardial infarction. Black participants had a 41.9% higher risk of the study outcome than non-Black participants (95% confidence interval = 1.01-1.95). TED with mental stress explained 69% of this excess risk. CONCLUSIONS: Among CHD patients, Black individuals are more likely than non-Black individuals to develop endothelial dysfunction with mental stress, which in turn explains a substantial portion of their excess risk of adverse events.

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.

Quantitation of diffuse myocardial ischemia with mental stress and its association with cardiovascular events in individuals with recent myocardial infarction.

Microcirculatory dysfunction during psychological stress may lead to diffuse myocardial ischemia. We developed a novel quantification method for diffuse ischemia during mental stress (dMSI) and examined its relationship with outcomes after a myocardial infarction (MI). We studied 300 patients ≤ 61 years of age (50% women) with a recent MI. Patients underwent myocardial perfusion imaging with mental stress and were followed for 5 years. dMSI was quantified from cumulative count distributions of rest and stress perfusion. Focal ischemia was defined in a conventional fashion. The main outcome was a composite outcome of recurrent MI, heart failure hospitalizations, and cardiovascular death. A dMSI increment of 1 standard deviation was associated with a 40% higher risk for adverse events (HR 1.4, 95% CI 1.2-1.5). Results were similar after adjustment for viability, demographic and clinical factors and focal ischemia. In sex-specific analysis, higher levels of dMSI (per standard deviation increment) were associated with 53% higher risk of adverse events in women (HR 1.5, 95% CI 1.2-2.0) but not in men (HR 0.9, 95% CI 0.5-1.4), P 0.001. A novel index of diffuse ischemia with mental stress was associated with recurrent events in women but not in men after MI.

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.

Child Maltreatment and Inflammatory Response to Mental Stress Among Adults Who Have Survived a Myocardial Infarction.

OBJECTIVE: Experiences of child maltreatment are associated with cardiovascular risk and disease in adulthood; however, the mechanisms underlying these associations are poorly understood. METHODS: We examined associations between retrospectively self-reported exposure to child maltreatment (Early Trauma Inventory Self-Report Short Form) and inflammatory responses to mental stress among adults (mean age = 50 years) who recently had a myocardial infarction ( n = 227). Inflammation was assessed as blood interleukin-6 (IL-6), matrix metalloproteinase-9 (MMP-9), and monocyte chemoattractant protein-1 concentrations, measured before and after a standardized public speaking stress task. We used mixed linear regression models adjusting for cardiovascular disease severity, medication usage, and psychosocial, demographic, and life-style factors. RESULTS: In women, increases in IL-6 levels and MMP-9 levels with stress were smaller in those exposed to sexual abuse, relative to those unexposed (IL-6 geometric mean increases = 1.6 [95% confidence interval {CI} = 1.4-1.9] pg/ml versus 2.1 [95% CI = 1.8-2.4] pg/ml; MMP-9 geometric mean increases = 1.0 [95% CI = 0.9-1.2] ng/ml versus 1.2 [95% CI = 1.1-1.4] ng/ml). No differences were noted for emotional or physical abuse. By contrast in men, individuals exposed to sexual abuse had larger IL-6 responses than those not exposed to abuse. CONCLUSIONS: These findings suggest sex differences in stress response among survivors of a myocardial infarction exposed to abuse early in life. They also underscore the importance of examining sex as an effect modifier of relationships between exposure to early life adversity and inflammatory responses to mental stressors in midlife.

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.

Impaired Peripheral Microvascular Function and Risk of Major Adverse Cardiovascular Events in Patients With Coronary Artery Disease.

[Figure: see text].

Associations Between Inflammation, Cardiovascular Regenerative Capacity, and Cardiovascular Events: A Cohort Study.

Objective: Circulating progenitor cells possess immune modulatory properties and might mitigate inflammation that is characteristic of patients with coronary artery disease. We hypothesized that patients with fewer circulating progenitor cells (CPCs) will have higher inflammatory markers and worse outcomes. Approach and Results: Patients with stable coronary artery disease were enrolled in a prospective study enumerating CPCs as CD (cluster of differentiation)-34-expressing mononuclear cells (CD34+) and inflammation as levels of IL (interleukin)-6 and high-sensitivity CRP (C-reactive protein) levels. Patients were followed for 5 years for the end points of death and myocardial infarction with repeat inflammatory biomarkers measured after a median of 2 years. In the entire cohort of 392 patients, IL-6 and high-sensitivity CRP levels remained unchanged (0.3+/-2.4 pg/mL and 0.1+/-1.0 mg/L; P=0.45) after 2 years. CPC counts (log-transformed) were inversely correlated with the change in IL-6 levels (r, -0.17; P<0.001). Using linear regression, IL-6 and high-sensitivity CRP levels declined by -0.59 (95% CI, -0.90 to -0.20) pg/mL and -0.13 (-0.28 to 0.01) mg/L per 1 log higher CPC counts after adjustment for the demographic and clinical variables, as well as medications. Using Cox models adjusted for these risk factors, a rise in 1 pg/mL of IL-6 was associated with a 11% (95% CI, 9-13) greater risk of death/myocardial infarction. We found that the change in IL6 level partly (by 40%) mediated the higher risk of adverse events among those with low CPC counts. Conclusions: Reduced cardiovascular regenerative capacity is independently associated with progressive inflammation in patients with coronary artery disease that in turn is associated with poor outcomes.

The association between baseline circulating progenitor cells and vascular function: The role of aging and risk factors.

BACKGROUND: To investigate the cross-sectional and longitudinal relationships between vascular function and circulating progenitor cell (CPC) counts with respect to aging and exposure to risk factors. METHODS: In 797 adult participants, CPCs were enumerated by flow cytometry as CD45med mononuclear cells expressing CD34 epitope and its subsets co-expressing CD133, and chemokine C-X-C motif receptor 4 (CXCR4+). Arterial stiffness was evaluated by tonometry-derived pulse wave velocity (PWV) and microvascular function was assessed as digital reactive hyperemia index (RHI). RESULTS: In cross-sectional analyses, for every doubling in CD34+ cell counts, PWV was 15% higher and RHI was 9% lower, after adjusting for baseline characteristics and risk factors (p for all < 0.01). There were significant CPC-by-age-by-risk factor interactions (p <0.05) for both vascular measures. Among younger subjects (< 48 years), CPC counts were higher in those with risk factors and vascular function was better in those with higher compared to those with lower CPC counts (p for all < 0.0l). In contrast, in older participants, CPCs were not higher in those with risk factors, and vascular function was worse compared to the younger age group. A lower CPC count at baseline was an independent predictor of worsening vascular function during 2-year follow-up. CONCLUSION: A higher CPC count in the presence of risk factors is associated with better vascular function among younger individuals. There is no increase in CPC count with risk factors in older individuals who have worse vascular function. Moreover, a higher CPC count is associated with less vascular dysfunction with aging.

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.

Mental Stress-Induced Myocardial Ischemia.

PURPOSE OF REVIEW: To summarize recent evidence on mental stress-induced myocardial ischemia (MSIMI), its mechanisms, and clinical significance. RECENT FINDINGS: MSIMI can occur in patients with normal cardiac stress testing, is only weakly related to severity of coronary artery disease (CAD), and it is often silent. Among patients with CAD, MSIMI is associated with a twofold increased risk of major adverse cardiovascular events compared to those who do not have MSIMI. Certain groups such as young women with myocardial infarction and those with psychological comorbidities are more susceptible to MSIMI. Abnormal microvascular vasoreactivity and inflammation are implicated mechanisms in MSIMI. Increased brain activity in regions that modulate autonomic reactivity to emotional stress and fear is associated with MSIMI. MSIMI has important prognostic implications in patients with CAD. Stress can no longer be ignored as a risk factor in cardiology care. Clinical trials testing effective strategies to target MSIMI are needed.

Higher Activation of the Rostromedial Prefrontal Cortex During Mental Stress Predicts Major Cardiovascular Disease Events in Individuals With Coronary Artery Disease.

BACKGROUND: Psychological stress is a risk factor for major adverse cardiovascular events (MACE) in individuals with coronary artery disease. Certain brain regions that control both emotional states and cardiac physiology may be involved in this relationship. The rostromedial prefrontal cortex (rmPFC) is an important brain region that processes stress and regulates immune and autonomic functions. Changes in rmPFC activity with emotional stress (reactivity) may be informative of future risk for MACE. METHODS: Participants with stable coronary artery disease underwent acute mental stress testing using a series of standardized speech/arithmetic stressors and simultaneous brain imaging with high-resolution positron emission tomography brain imaging. We defined high rmPFC activation as a difference between stress and control scans greater than the median value for the entire cohort. Interleukin-6 levels 90 minutes after stress, and high-frequency heart rate variability during stress were also assessed. We defined MACE as a composite of cardiovascular death, myocardial infarction, unstable angina with revascularization, and heart failure hospitalization. RESULTS: We studied 148 subjects (69% male) with mean±SD age of 62±8 years. After adjustment for baseline demographics, risk factors, and baseline levels of interleukin-6 and high-frequency heart rate variability, higher rmPFC stress reactivity was independently associated with higher interleukin-6 and lower high-frequency heart rate variability with stress. During a median follow-up of 3 years, 34 subjects (21.3%) experienced a MACE. Each increase of 1 SD in rmPFC activation with mental stress was associated with a 21% increase risk of MACE (hazard ratio, 1.21 [95% CI, 1.08-1.37]). Stress-induced interleukin-6 and high-frequency heart rate variability explained 15.5% and 32.5% of the relationship between rmPFC reactivity and MACE, respectively. Addition of rmPFC reactivity to conventional risk factors improved risk reclassification for MACE prediction, and C-statistic improved from 0.71 to 0.76 (P=0.03). CONCLUSIONS: Greater rmPFC stress reactivity is associated with incident MACE. Immune and autonomic responses to mental stress may play a contributory role.

Everyday Discrimination and Mental Stress-Induced Myocardial Ischemia.

OBJECTIVE: Mental stress-induced myocardial ischemia (MSIMI), a transient myocardial ischemic response to mental stress, is associated with poorer outcomes among patients with coronary heart disease and is more likely to occur among women. However, predictors of MSIMI are not well explored. The current study investigated the association between experiences of everyday discrimination and MSIMI among patients with recent myocardial ischemia and contrasted the results with conventional stress-induced myocardial ischemia (CSIMI). We examined sex differences in associations. METHODS: We studied 295 post-MI patients (145 women, 150 men). Provocation of myocardial ischemia with mental stress (speech task) and conventional stress (exercise or pharmacologic) was assessed by myocardial perfusion imaging. Frequency of exposure to everyday discrimination was assessed via questionnaire using the Everyday Discrimination Scale (EDS). RESULTS: The mean age was 51 years in both women and men, and the EDS score ranged from 10 to 38 (mean [standard deviation] = 17 [6] years). After multivariable analysis, each standard deviation increase in the EDS score (more frequent exposure) was associated with an increased odds of MSIMI (odds ratio [OR] = 1.57 [1.10-2.23]). The EDS score was not associated with CSIMI (OR = 0.86 [0.64-1.17]). Women demonstrated a twofold increase (OR = 1.96 [1.13-3.38], p = .02) in the adjusted odds of MSIMI, with each standard deviation increase in the EDS score compared with a 1.4-fold increase (OR = 1.40 [0.80-2.44], p = .24) among men; however, interaction was not statistically significant. CONCLUSIONS: Among post-MI patients, everyday discrimination was positively associated with occurrence of MSIMI, but not with CSIMI; associations were more pronounced among women.

Noninvasive Cervical Vagal Nerve Stimulation Alters Brain Activity During Traumatic Stress in Individuals With Posttraumatic Stress Disorder.

OBJECTIVE: Posttraumatic stress disorder (PTSD) is a disabling condition affecting a large segment of the population; however, current treatment options have limitations. New interventions that target the neurobiological alterations underlying symptoms of PTSD could be highly beneficial. Transcutaneous cervical (neck) vagal nerve stimulation (tcVNS) has the potential to represent such an intervention. The goal of this study was to determine the effects of tcVNS on neural responses to reminders of traumatic stress in PTSD. METHODS: Twenty-two participants were randomized to receive either sham (n = 11) or active (n = 11) tcVNS stimulation in conjunction with exposure to neutral and personalized traumatic stress scripts with high-resolution positron emission tomography scanning with radiolabeled water for brain blood flow measurements. RESULTS: Compared with sham, tcVNS increased brain activations during trauma scripts (p < .005) within the bilateral frontal and temporal lobes, left hippocampus, posterior cingulate, and anterior cingulate (dorsal and pregenual), and right postcentral gyrus. Greater deactivations (p < .005) with tcVNS were observed within the bilateral frontal and parietal lobes and left thalamus. Compared with tcVNS, sham elicited greater activations (p < .005) in the bilateral frontal lobe, left precentral gyrus, precuneus, and thalamus, and right temporal and parietal lobes, hippocampus, insula, and posterior cingulate. Greater (p < .005) deactivations were observed with sham in the right temporal lobe, posterior cingulate, hippocampus, left anterior cingulate, and bilateral cerebellum. CONCLUSIONS: tcVNS increased anterior cingulate and hippocampus activation during trauma scripts, potentially indicating a reversal of neurobiological changes with PTSD consistent with improved autonomic control.Trial Registration: No. NCT02992899.

A Multi-center Genome-wide Association Study of Cervical Dystonia.

BACKGROUND: Several monogenic causes for isolated dystonia have been identified, but they collectively account for only a small proportion of cases. Two genome-wide association studies have reported a few potential dystonia risk loci; but conclusions have been limited by small sample sizes, partial coverage of genetic variants, or poor reproducibility. OBJECTIVE: To identify robust genetic variants and loci in a large multicenter cervical dystonia cohort using a genome-wide approach. METHODS: We performed a genome-wide association study using cervical dystonia samples from the Dystonia Coalition. Logistic and linear regressions, including age, sex, and population structure as covariates, were employed to assess variant- and gene-based genetic associations with disease status and age at onset. We also performed a replication study for an identified genome-wide significant signal. RESULTS: After quality control, 919 cervical dystonia patients compared with 1491 controls of European ancestry were included in the analyses. We identified one genome-wide significant variant (rs2219975, chromosome 3, upstream of COL8A1, P-value 3.04 × 10-8 ). The association was not replicated in a newly genotyped sample of 473 cervical dystonia cases and 481 controls. Gene-based analysis identified DENND1A to be significantly associated with cervical dystonia (P-value 1.23 × 10-6 ). One low-frequency variant was associated with lower age-at-onset (16.4 ± 2.9 years, P-value = 3.07 × 10-8 , minor allele frequency = 0.01), located within the GABBR2 gene on chromosome 9 (rs147331823). CONCLUSION: The genetic underpinnings of cervical dystonia are complex and likely consist of multiple distinct variants of small effect sizes. Larger sample sizes may be needed to provide sufficient statistical power to address the presumably multi-genic etiology of cervical dystonia. © 2021 International Parkinson and Movement Disorder Society.

Peripheral Vasoconstriction During Mental Stress and Adverse Cardiovascular Outcomes in Patients With Coronary Artery Disease.

RATIONALE: Excessive vasoconstriction in response to mental stress may be a potential mechanism by which acute psychological stress leads to adverse cardiac events. OBJECTIVES: We investigated whether excessive digital vasoconstriction during acute mental stress predicts adverse cardiovascular outcomes among patients with coronary artery disease. METHODS AND RESULTS: Five hundred forty-nine patients with stable coronary artery disease (age 63±9, 76% male, 29% black) underwent mental stress testing with a standardized public speaking stressor and followed prospectively for cardiovascular end points. Digital pulse wave amplitude was continuously measured using peripheral artery tonometry (PAT, Itamar Inc). Stress/rest PAT ratio (sPAT) of pulse wave amplitude during mental stress/baseline was calculated and dichotomized by the median value into low and high sPAT ratio groups. Upon 3-year follow-up, Fine and Gray's subdistribution hazard ratios were used to examine the association between sPAT ratio and the composite end point of cardiovascular death, myocardial infarction, revascularization, and hospitalization for heart failure. The median sPAT ratio was 0.68 (interquartile range, 0.48-0.88), indicating 32% vasoconstriction with mental stress. Men were more likely to have low sPAT ratio than women (odds ratio, 1.79; P=0.007) while those on ß-blockers were less likely to have low sPAT ratio (odds ratio, 0.52; P=0.003). After adjusting for demographic and cardiovascular risk factors, medications, and rate-pressure product change during mental stress, those with low sPAT ratio were at significantly higher risk of adverse outcomes (subdistribution hazard ratio, 1.77 [95% CI, 1.12-2.80]). CONCLUSIONS: Greater peripheral vasoconstriction with mental stress, denoted by a low sPAT ratio, is associated with a higher risk of adverse cardiovascular outcomes in patients with coronary artery disease.