Anxiety and depression are associated with heightened risk of incident deep vein thrombosis: Mediation through stress-related neural mechanisms.

Controversy exists as to whether anxiety and depression increase deep vein thrombosis (DVT) risk, and the mechanisms mediating potential links remain unknown. We aimed to evaluate the association between anxiety and depression and DVT risk and determine whether upregulated stress-related neural activity (SNA), which promotes chronic inflammation, contributes to this link. Our retrospective study included adults (N = 118 871) enrolled in Mass General Brigham Biobank. A subset (N = 1520) underwent clinical 18F-FDG-PET/CT imaging. SNA was measured as the ratio of amygdalar to cortical activity (AmygAC). High-sensitivity C-reactive protein (hs-CRP) and heart rate variability (HRV) were also obtained. Median age was 58 [interquartile range (IQR) 42-70] years with 57% female participants. DVT occurred in 1781 participants (1.5%) over median follow-up of 3.6 years [IQR 2.1-5.2]. Both anxiety and depression independently predicted incident DVT risk after robust adjustment (HR [95% CI]: 1.53 [1.38-1.71], p < .001; and 1.48 [1.33-1.65], p < .001, respectively). Additionally, both anxiety and depression associated with increased AmygAC (standardized beta [95% CI]: 0.16 [0.04-0.27], p = .007, and 0.17 [0.05-0.29], p = .006, respectively). Furthermore, AmygAC associated with incident DVT (HR [95% CI]: 1.30 [1.07-1.59], p = .009). Mediation analysis demonstrated that the link between anxiety/depression and DVT was mediated by: (1) higher AmygAC, (2) higher hs-CRP, and (3) lower HRV ( < .05 for each). Anxiety and depression confer an attributable risk of DVT similar to other traditional DVT risk factors. Mechanisms appear to involve increased SNA, autonomic system activity, and inflammation. Future studies are needed to determine whether treatment of anxiety and depression can reduce DVT risk.

Cortico-limbic interactions and carotid atherosclerotic burden during chronic stress exposure.

BACKGROUND AND AIMS: Chronic stress associates with cardiovascular disease, but mechanisms remain incompletely defined. Advanced imaging was used to identify stress-related neural imaging phenotypes associated with atherosclerosis. METHODS: Twenty-seven individuals with post-traumatic stress disorder (PTSD), 45 trauma-exposed controls without PTSD, and 22 healthy controls underwent 18F-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging (18F-FDG PET/MRI). Atherosclerotic inflammation and burden were assessed using 18F-FDG PET (as maximal target-to-background ratio, TBR max) and MRI, respectively. Inflammation was assessed using high-sensitivity C-reactive protein (hsCRP) and leucopoietic imaging (18F-FDG PET uptake in spleen and bone marrow). Stress-associated neural network activity (SNA) was assessed on 18F-FDG PET as amygdala relative to ventromedial prefrontal cortex (vmPFC) activity. MRI diffusion tensor imaging assessed the axonal integrity (AI) of the uncinate fasciculus (major white matter tract connecting vmPFC and amygdala). RESULTS: Median age was 37 years old and 54% of participants were female. There were no significant differences in atherosclerotic inflammation between participants with PTSD and controls; adjusted mean difference in TBR max (95% confidence interval) of the aorta 0.020 (-0.098, 0.138), and of the carotids 0.014 (-0.091, 0.119). Participants with PTSD had higher hsCRP, spleen activity, and aorta atherosclerotic burden (normalized wall index). Participants with PTSD also had higher SNA and lower AI. Across the cohort, carotid atherosclerotic burden (standard deviation of wall thickness) associated positively with SNA and negatively with AI independent of Framingham risk score. CONCLUSIONS: In this study of limited size, participants with PTSD did not have higher atherosclerotic inflammation than controls. Notably, impaired cortico-limbic interactions (higher amygdala relative to vmPFC activity or disruption of their intercommunication) associated with carotid atherosclerotic burden. Larger studies are needed to refine these findings.

Effect of Stress-Related Neural Pathways on the Cardiovascular Benefit of Physical Activity.

BACKGROUND: The mechanisms underlying the psychological and cardiovascular disease (CVD) benefits of physical activity (PA) are not fully understood. OBJECTIVES: This study tested whether PA: 1) attenuates stress-related neural activity, which is known to potentiate CVD and for its role in anxiety/depression; 2) decreases CVD in part through this neural effect; and 3) has a greater impact on CVD risk among individuals with depression. METHODS: Participants from the Mass General Brigham Biobank who completed a PA survey were studied. A subset underwent 18F-fluorodeoxyglucose positron emission tomography/computed tomographic imaging. Stress-related neural activity was measured as the ratio of resting amygdalar-to-cortical activity (AmygAC). CVD events were ascertained from electronic health records. RESULTS: A total of 50,359 adults were included (median age 60 years [Q1-Q3: 45-70 years]; 40.1% male). Greater PA was associated with both lower AmygAC (standardized ß: -0.245; 95% CI: -0.444 to -0.046; P = 0.016) and CVD events (HR: 0.802; 95% CI: 0.719-0.896; P < 0.001) in multivariable models. AmygAC reductions partially mediated PA's CVD benefit (OR: 0.96; 95% CI: 0.92-0.99; P < 0.05). Moreover, PA's benefit on incident CVD events was greater among those with (vs without) preexisting depression (HR: 0.860; 95% CI: 0.810-0.915; vs HR: 0.929; 95% CI: 0.910-0.949; P interaction = 0.011). Additionally, PA above guideline recommendations further reduced CVD events, but only among those with preexisting depression (P interaction = 0.023). CONCLUSIONS: PA appears to reduce CVD risk in part by acting through the brain's stress-related activity; this may explain the novel observation that PA reduces CVD risk to a greater extent among individuals with depression.

PTSD increases risk for major adverse cardiovascular events through neural and cardio-inflammatory pathways.

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], ß = 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.

Reduced Stress-Related Neural Network Activity Mediates the Effect of Alcohol on Cardiovascular Risk.

BACKGROUND: Chronic stress associates with major adverse cardiovascular events (MACE) via increased stress-related neural network activity (SNA). Light/moderate alcohol consumption (ACl/m) has been linked to lower MACE risk, but the mechanisms are unclear. OBJECTIVES: The purpose of this study was to evaluate whether the association between ACl/m and MACE is mediated by decreased SNA. METHODS: Individuals enrolled in the Mass General Brigham Biobank who completed a health behavior survey were studied. A subset underwent 18F-fluorodeoxyglucose positron emission tomography, enabling assessment of SNA. Alcohol consumption was classified as none/minimal, light/moderate, or high (<1, 1-14, or >14 drinks/week, respectively). RESULTS: Of 53,064 participants (median age 60 years, 60% women), 23,920 had no/minimal alcohol consumption and 27,053 ACl/m. Over a median follow-up of 3.4 years, 1,914 experienced MACE. ACl/m (vs none/minimal) associated with lower MACE risk (HR: 0.786; 95% CI: 0.717-0.862; P < 0.0001) after adjusting for cardiovascular risk factors. In 713 participants with brain imaging, ACl/m (vs none/minimal) associated with decreased SNA (standardized beta -0.192; 95% CI: -0.338 to -0.046; P = 0.01). Lower SNA partially mediated the beneficial effect of ACl/m on MACE (log OR: -0.040; 95% CI: -0.097 to -0.003; P < 0.05). Further, ACl/m associated with larger decreases in MACE risk among individuals with (vs without) prior anxiety (HR: 0.60 [95% CI: 0.50-0.72] vs 0.78 [95% CI: 0.73-0.80]; P interaction = 0.003). CONCLUSIONS: ACl/m associates with reduced MACE risk, in part, by lowering activity of a stress-related brain network known for its association with cardiovascular disease. Given alcohol's potential health detriments, new interventions with similar effects on SNA are needed.

Vitamin D Supplementation and Fractures in Adults: A Systematic Umbrella Review of Meta-Analyses of Controlled Trials.

CONTEXT: The growing number of systematic reviews/meta-analyses (SR/MAs) on vitamin D (±â€…calcium) for fracture prevention has led to contradictory guidelines. OBJECTIVE: This umbrella review aims to assess the quality and explore the reasons for the discrepancy of SR/MAs of trials on vitamin D supplementation for fracture risk reduction in adults. METHODS: We searched 4 databases (2010-2020), Epistemonikos, and references of included SRs/MAs, and we contacted experts in the field. We used A MeaSurement Tool to Assess systematic Reviews 2 (AMSTAR-2) for quality assessment. We compared results and investigated reasons for discordance using matrices and subgroup analyses (PROSPERO registration: CRD42019129540). We included 13 SR/MAs on vitamin D and calcium (Ca/D) and 19 SR/MAs on vitamin D alone, compared to placebo/control. RESULTS: Only 2 from 10 SRs/MAs on Ca/D were of moderate quality. Ca/D reduced the risk of hip fractures in 8 of 12 SRs/MAs (relative risk [RR] 0.61-0.84), and any fractures in 7 of 11 SR/MAs (RR 0.74-0.95). No fracture risk reduction was noted in SRs/MAs exclusively evaluating community-dwelling individuals or in those on vitamin D alone compared to placebo/control. Discordance in results between SRs/MAs stems from inclusion of different trials, related to search periods and eligibility criteria, and varying methodology (using intention to treat, per-protocol, or complete case analysis from individual trials). CONCLUSION: Ca/D reduces the risk of hip and any fractures, possibly driven by findings from institutionalized individuals. Individual participant data meta-analyses of patients on Ca/D with sufficient follow-up periods, and subgroup analyses, would unravel determinants for a beneficial response to supplementation.

Risk of Postoperative Renal Failure in Radical Nephrectomy and Nephroureterectomy: A Validated Risk Prediction Model.

INTRODUCTION: The study aimed to construct and validate a risk prediction model for incidence of postoperative renal failure (PORF) following radical nephrectomy and nephroureterectomy. METHODS: The American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database years 2005-2014 were used for the derivation cohort. A stepwise multivariate logistic regression analysis was conducted, and the final model was validated with an independent cohort from the ACS-NSQIP database years 2015-2017. RESULTS: In cohort of 14,519 patients, 296 (2.0%) developed PORF. The final 9-factor model included age, gender, diabetes, hypertension, BMI, preoperative creatinine, hematocrit, platelet count, and surgical approach. Model receiver-operator curve analysis provided a C-statistic of 0.79 (0.77, 0.82; p < 0.001), and overall calibration testing R2 was 0.99. Model performance in the validation cohort provided a C-statistic of 0.79 (0.76, 0.81; p < 0.001). CONCLUSION: PORF is a known risk factor for chronic kidney disease and cardiovascular morbidity, and is a common occurrence after unilateral kidney removal. The authors propose a robust and validated risk prediction model to aid in identification of high-risk patients and optimization of perioperative care.

Exercise-Induced Ventricular Ectopy and Cardiovascular Mortality in Asymptomatic Individuals.

BACKGROUND: The prognosis of exercise-induced premature ventricular contractions (PVCs) in asymptomatic individuals is unclear. OBJECTIVES: This study sought to investigate whether high-grade PVCs during stress testing predict mortality in asymptomatic individuals. METHODS: A cohort of 5,486 asymptomatic individuals who took part in the Lipid Research Clinics prospective cohort had baseline interview, physical examination, blood tests, and underwent Bruce protocol treadmill testing. Adjusted Cox survival models evaluated the association of exercise-induced high-grade PVCs (defined as either frequent (>10 per minute), multifocal, R-on-T type, or ≥2 PVCs in a row) with all-cause and cardiovascular mortality. RESULTS: Mean baseline age was 45.4 ± 10.8 years; 42% were women. During a mean follow-up of 20.2 ± 3.9 years, 840 deaths occurred, including 311 cardiovascular deaths. High-grade PVCs occurred during exercise in 1.8% of individuals, during recovery in 2.4%, and during both in 0.8%. After adjusting for age, sex, diabetes, hypertension, lipids, smoking, body mass index, and family history of premature coronary disease, high-grade PVCs during recovery were associated with cardiovascular mortality (hazard ratio [HR]: 1.82; 95% CI: 1.19-2.79; P = 0.006), which remained significant after further adjusting for exercise duration, heart rate recovery, achieving target heart rate, and ST-segment depression (HR: 1.68; 95% CI: 1.09-2.60; P = 0.020). Results were similar by clinical subgroups. High-grade PVCs occurring during the exercise phase were not associated with increased risk. Recovery PVCs did not improve 20-year cardiovascular mortality risk discrimination beyond clinical variables. CONCLUSIONS: High-grade PVCs occurring during recovery were associated with long-term risk of cardiovascular mortality in asymptomatic individuals, whereas PVCs occurring only during exercise were not associated with increased risk.

The association of cardiovascular mortality with a first-degree family member history of different cardiovascular diseases.

OBJECTIVE: To investigate which history of cardiovascular disease [coronary heart disease (CHD), stroke, or peripheral arterial disease] in a first-degree family member predicts cardiovascular mortality. METHODS: We studied a prospective cohort (the Lipid Research Clinics Prevalence Study) from ten primary care centers across North America. The primary outcome was cardiovascular mortality, assessed using Cox survival models. RESULTS: There were 8,646 participants (mean age: 47.4 ± 12.1 years, 46% women, 52% of participants with hyperlipidemia) who were followed up for a mean duration of 19.4 ± 4.9 years. There were 1,851 deaths (21%), including 852 cardiovascular deaths. A paternal, maternal or sibling history of premature CHD (before 60 years) was present in 26% of participants, of stroke in 27% of participants, and of peripheral arterial disease in 24% of participants. After adjusting for risk factors (age, sex, systolic blood pressure, diastolic blood pressure, body mass index, smoking, fasting glucose, low-density lipoprotein cholesterol and triglycerides), only a paternal history of premature or any CHD, a maternal history of diabetes mellitus or premature or any CHD, and a sibling history of premature CHD, hypertension, or hyperlipidemia were individually predictive of cardiovascular mortality. After adjusting for risk factors and the mentioned familial factors, only paternal and maternal histories of CHD, especially before 60 years, remained predictive of cardiovascular mortality, with a somewhat higher association for a maternal history [adjusted hazard ratio (aHR) = 1.99, 95% CI: 1.36-2.92,P < 0.001 for maternal history of premature CHD; aHR = 1.52, 95% CI: 1.10-2.10, P = 0.011 for paternal history of premature CHD]. Family history of stroke or peripheral arterial disease did not predict cardiovascular mortality. Parental history of premature CHD predicted cardiovascular mortality independently of baseline age (< 60 years and ≥ 60 years), hypertension, or hyperlipidemia and carried more important prognostic value in men rather than women. CONCLUSIONS: In this study, a parental history of CHD, especially before 60 years, best predicted cardiovascular mortality. This finding could help more accurately identify high-risk patients who would benefit from preventive strategies.