Objective:Individuals with posttraumatic stress disorder (PTSD) are significantly more likely to be diagnosed with cardiovascular disease (CVD) (e.g., myocardial infarction, stroke). The evidence for ...this link is so compelling that the National Institutes of Health convened a working group to determine gaps in the literature, including the need for large-scale genomic studies to identify shared genetic risk. The aim of the present study was to address some of these gaps by utilizing PTSD and CVD genome-wide association study (GWAS) summary statistics in a large biobank sample to determine the shared genetic risk of PTSD and CVD.Methods:A large health care biobank data set was used (N=36,412), combined with GWAS summary statistics from publicly available large-scale PTSD and CVD studies. Disease phenotypes (e.g., PTSD) were collected from electronic health records. De-identified genetic data from the biobank were genotyped using Illumina SNP array. Summary statistics data sets were processed with the following quality-control criteria: 1) SNP heritability h2 >0.05, 2) compute z-statistics (z=beta/SE or z=log(OR)/SE), 3) filter nonvariable SNPs (0<freq<1), and 4) filter SNPs with low number of samples. The multitrait analysis of GWAS (MTAG) approach was used to combine GWAS summary statistics.Results:Significant genetic correlations were found between PTSD and CVD (rG=0.24, SE=0.06), and Mendelian randomization analyses indicated a potential causal link from PTSD to hypertension (β=0.20, SE=0.04), but not the reverse. PTSD summary statistics significantly predicted PTSD diagnostic status (R2=0.27), and this was significantly improved by incorporating summary statistics from CVD and major depressive disorder (R2=1.30). Further, pathway enrichment analyses indicated that genetic variants involved in shared PTSD-CVD risk included those involved in postsynaptic structure, synapse organization, and interleukin-7-mediated signaling pathways.Conclusions:The results from this study suggest that PTSD and CVD may share genetic risk. Further, these results implicate PTSD as a risk factor leading to the development of hypertension and coronary artery disease. Additional research is needed to determine the clinical utility of these findings.
Prior observational studies have suggested that medications targeting the renin-angiotensin system, such as angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs), ...may be associated with decreased PTSD symptoms. Given known sex differences in PTSD prevalence and cardiovascular disease, here we tested whether the effects of ACE-I/ARB status on PTSD differ by sex. We also expanded these observations with replication analyses in a large biorepository database. Participants in the initial sample included 840 trauma-exposed individuals recruited as part of the Grady Trauma Project. The Modified PTSD Symptom Scale (M-PSS) was administered and ACE-I/ARB status was determined by self-report. Replication analyses were conducted using a large biorepository database (Partners Healthcare Biobank, N = 116,389) with diagnoses and medication status based on available electronic health records. Among individuals treated with ACE-Is/ARBs in the initial sample, women had significantly higher M-PSS total and Re-experiencing severity compared to men (p's < 0.05). Analyses with the large biorepository sample robustly replicated the overall effects of ACE-I/ARB medication associated with lower rate of PTSD diagnosis (p < 0.001). We also demonstrated that this effect may be specific to the renin-angiotensin system as it did not replicate for beta-blockers, calcium channel blockers, or diuretics. When we examined more specific drug classes, results indicated that the ACE-I/ARB effect on PTSD may be driven more by ARBs (e.g., Losartan) than by ACE-Is. Post-hoc analyses indicated that racial differences may exist in these effects. Overall, our results replicate and extend prior observations that the renin-angiotensin system is associated with PTSD. Medications targeting this system may be worthy of further investigation for PTSD treatment. Our findings suggest that sex and race effects should be considered in future treatment research.
•The current study tested neuro-immune mechanisms of PTSD and cardiovascular risk.•Data from a hospital biobank included neural, autonomic, and inflammatory activity.•PTSD predicted MACE; this was ...mediated by neuro-immune mechanisms.•Neuro-immune pathways are likely mechanisms linking PTSD to MACE.
While posttraumatic stress disorder (PTSD) is known to associate with an elevated risk for major adverse cardiovascular events (MACE), few studies have examined mechanisms underlying this link. Recent studies have demonstrated that neuro-immune mechanisms, (manifested by heightened stress-associated neural activity (SNA), autonomic nervous system activity, and inflammation), link common stress syndromes to MACE. However, it is unknown if neuro-immune mechanisms similarly link PTSD to MACE. The current study aimed to test the hypothesis that upregulated neuro-immune mechanisms increase MACE risk among individuals with PTSD. This study included N = 118,827 participants from a large hospital-based biobank. Demographic, diagnostic, and medical history data collected from the biobank. SNA (n = 1,520), heart rate variability (HRV; n = 11,463), and high sensitivity C-reactive protein (hs-CRP; n = 15,164) were obtained for a subset of participants. PTSD predicted MACE after adjusting for traditional MACE risk factors (hazard ratio (HR) 95 % confidence interval (CI) = 1.317 1.098, 1.580, β = 0.276, p = 0.003). The PTSD-to-MACE association was mediated by SNA (CI = 0.005, 0.133, p < 0.05), HRV (CI = 0.024, 0.056, p < 0.05), and hs-CRP (CI = 0.010, 0.040, p < 0.05). This study provides evidence that neuro-immune pathways may play important roles in the mechanisms linking PTSD to MACE. Future studies are needed to determine if these markers are relevant targets for PTSD treatment and if improvements in SNA, HRV, and hs-CRP associate with reduced MACE risk in this patient population.
Posttraumatic stress disorder (PTSD) has long been associated with a heightened risk of cardiovascular disease (CVD). A number of mechanisms have been implicated to underlie this brain–heart axis ...relationship, such as altered functioning of the autonomic nervous system and increased systemic inflammation. While neural alterations have repeatedly been observed in PTSD, they are rarely considered in the PTSD–CVD link. The brain–heart axis is a pathway connecting frontal and limbic brain regions to the brainstem and periphery via the autonomic nervous system and it may be a promising model for understanding CVD risk in PTSD given its overlap with PTSD neural deficits. We first provide a summary of the primary mechanisms implicated in the association between PTSD and CVD. We then review the brain–heart axis and its relevance to PTSD, as well as findings from PTSD trials demonstrating that a number of PTSD treatments have effects on areas of the brain–heart axis. Finally, we discuss sex considerations in the PTSD–CVD link. A critical next step in this study is to determine if PTSD treatments that affect the brain–heart axis (e.g., brain stimulation that improves autonomic function) also reduce the risk of CVD.
Despite its prevalence, sexual assault remains a vastly underreported crime. Previous research suggests that engagement in certain types of resistance during an assault affects the way in which both ...victims and others perceive the attack; such perceptions influence victims’ likelihood of reporting the assault to law enforcement as well as the criminal justice system response to reported allegations. Using a fight/flight/freeze theoretical framework, the current study sought to examine how forceful, nonforceful, and freeze responding influenced victim reporting and the extent to which reported assaults were pursued and investigated by law enforcement. Using data from the National Crime Victimization Survey between 2010 and 2016, logistic regression analysis indicated that victims are significantly less likely to report to law enforcement if they froze during the attack. Interestingly, although engagement in forceful resistance increases victims’ likelihood of reporting to law enforcement, it has no bearing on law enforcement response beyond the effect of physical injury. Rather, physical injury (e.g., bruises, cuts, broken bones) is the only predictor of law enforcement response to sexual assault allegations. Findings suggest that whereas fight and freeze responses to sexual victimization influence victims’ willingness to report to law enforcement, resistance is not uniquely predictive of law enforcement response once physical injury is considered.
Objective: Research suggests that 4-factor models of posttraumatic stress disorder (PTSD) may be improved upon by the addition of novel factors, such as Dysphoric Arousal, Externalizing Behaviors, ...and Anhedonia. However, a novel 7-factor hybrid model has demonstrated superior fit in veteran and undergraduate samples. The current study sought to replicate this finding in a trauma-exposed community sample and examined relations with positive (PA) and negative affect (NA). Method: Participants included 403 adults (Mage = 37.75) recruited through Amazon's MTurk. PTSD was measured using the PTSD Checklist-5 (PCL-5). Confirmatory factor analyses were conducted in Mplus. Results: The 7-factor hybrid model demonstrated good fit: CFI = .96, TLI = .95, RMSEA = .06 (90% CI .05, .07), SRMR = .03. This model was superior to the 5- and 6-factor models. All factors demonstrated significant relations with PA and NA, the largest of which were the Externalizing Behaviors (with NA) and Anhedonia (with PA) factors. Conclusion: Results provide support for the 7-factor hybrid model of PTSD using the PCL-5 in a community sample. Findings replicate previous research suggesting that PTSD is highly related to NA, which has been purported as an underlying dimension of PTSD. It is recommended that future research use clinical measures to further examine the hybrid model.
Posttraumatic stress disorder (PTSD) is associated with autonomic dysfunction as indicated by deficits in the sympathetic and parasympathetic nervous systems. These abnormalities are expressed as ...elevated heart rate and reduced heart rate variability (HRV), respectively. Intermittent theta-burst stimulation (iTBS), a form of transcranial magnetic stimulation, has demonstrated effectiveness in PTSD. Nevertheless, it remains unclear whether HRV may be an iTBS biomarker for PTSD and whether iTBS impacts autonomic activity.
Fifty veterans with PTSD participated in a randomized controlled trial, receiving ten daily sessions of sham-controlled iTBS (right dorsolateral prefrontal cortex, 1800 pulses/day, 80% active motor threshold, 9.5 min). With a usable dataset (N = 47), HRV parameters were assessed as predictors of clinical response immediately after stimulation. iTBS effects on autonomic response (mean RR interval, root mean square of successive differences RMSSD, total power TP, and low-frequency/high-frequency LF/HF ratio) were evaluated using an ultra-short approach.
TP and RMSSD were significant predictors of acute clinical response to iTBS. Individuals with higher TP had better response to iTBS with improved symptoms on the Clinician-Administered PTSD Scale (rs = −0.58, p = 0.004), and higher functionality on the Social and Occupational Function Scale (rs = 0.43, p = 0.04). Similarly, higher RMSSD was associated with superior outcomes (rs = −0.44, p = 0.04). No other significant changes in HRV metrics were observed (p ≥ 0.05).
Our findings indicate that autonomic activity is a potential low-cost and technically simple predictive biomarker of iTBS response in PTSD. Less autonomic dysfunction was associated with superior clinical improvements with iTBS. Future studies might consider HRV acquisition during iTBS, as well as prospective testing of these findings in patients with elevated hyperarousal.
Evidence-based pharmacological treatments for posttraumatic stress disorder (PTSD) are few and of limited efficacy. Previous work suggests that angiotensin type 1 receptor inhibition facilitates fear ...inhibition and extinction, important for recovery from PTSD. This study tests the efficacy of the angiotensin type 1 receptor antagonist losartan, an antihypertensive drug, repurposed for the treatment of PTSD.
A randomized controlled trial was conducted for 10 weeks in 149 men and women meeting DSM-5 PTSD criteria. Losartan (vs. placebo) was flexibly titrated from 25 to 100 mg/day by week 6 and held at highest tolerated dose until week 10. Primary outcome was the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) change score at 10 weeks from baseline. A key secondary outcome was change in CAPS-5 associated with a single nucleotide polymorphism of the ACE gene. Additional secondary outcomes included changes in the PTSD Checklist for DSM-5 and the Patient Health Questionnaire-9, and proportion of responders with a Clinical Global Impressions–Improvement scale of “much improved” or “very much improved.”
Both groups had robust improvement in PTSD symptoms, but there was no significant difference on the primary end point, CAPS-5 measured as week 10 change from baseline, between losartan and placebo (mean change difference, 0.9, 95% confidence interval, −3.2 to 5.0). There was no significant difference in the proportion of Clinical Global Impressions–Improvement scale responders for losartan (58.6%) versus placebo (57.9%), no significant differences in changes in PTSD Checklist for DSM-5 or Patient Health Questionnaire-9, and no association between ACE genotype and CAPS-5 improvement on losartan.
At these doses and durations, there was no significant benefit of losartan compared with placebo for the treatment of PTSD. We discuss implications for failure to determine the benefit of a repurposed drug with strong a priori expectations of success based on preclinical and epidemiological data.
Translational models of fear have greatly informed our understanding of PTSD and its underlying fear circuitry. One of the most replicated findings in the field is the two-fold higher PTSD incidence ...in females compared to males. While sociocultural factors play a role, the most robust biological influencers to date are gonadal hormones, such as estradiol and progesterone, which fluctuate across the menstrual cycle. Among studies that account for these hormones, most do so in isolation or collect both and only report one. Variation in study findings suggests that the ratio between these two hormones (the P/E ratio) may be an important and missing variable to further understand gonadal hormone influences on fear. Here we review cross-species examinations of fear and PTSD, within the contexts of estradiol and progesterone as well as P/E ratios that were calculated based on extant literature. We then provide recommendations for best practices in assay methods and reporting to improve research on the P/E ratio in fear and PTSD. Ultimately, greater understanding of this important variable will advance efforts to characterize gonadal hormone influences on fear learning processes in humans and animals.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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