Anxiety and Depression Associated With Increased Cardiovascular Disease Risk Through Accelerated Development of Risk Factors.

Background: Prior studies have incompletely assessed whether the development of cardiometabolic risk factors (CVDRF) (hypertension, hyperlipidemia, and diabetes mellitus) mediates the association between anxiety and depression (anxiety/depression) and cardiovascular disease (CVD). Objectives: The authors aimed to evaluate the following: 1) the association between anxiety/depression and incident CVDRFs and whether this association mediates the increased CVD risk; and 2) whether neuro-immune mechanisms and age and sex effects may be involved. Methods: Using a retrospective cohort design, Mass General Brigham Biobank subjects were followed for 10 years. Presence and timing of anxiety/depression, CVDRFs, and CVD were determined using ICD codes. Stress-related neural activity, chronic inflammation, and autonomic function were measured by the assessment of amygdalar-to-cortical activity ratio, high-sensitivity CRP, and heart rate variability. Multivariable regression and mediation analyses were employed. Results: Among 71,214 subjects (median age 49.6 years; 55.3% female), 27,048 (38.0%) developed CVDRFs during follow-up. Pre-existing anxiety/depression associated with increased risk of incident CVDRF (OR: 1.71 [95% CI: 1.59-1.83], P < 0.001) and with a shorter time to their development (ß = -0.486 [95% CI: -0.62 to -0.35], P < 0.001). The development of CVDRFs mediated the association between anxiety/depression and CVD events (log-odds: 0.044 [95% CI: 0.034-0.055], P < 0.05). Neuro-immune pathways contributed to the development of CVDRFs (P < 0.05 each) and significant age and sex effects were noted: younger women experienced the greatest acceleration in the development of CVDRFs after anxiety/depression. Conclusions: Anxiety/depression accelerate the development of CVDRFs. This association appears to be most notable among younger women and may be mediated by stress-related neuro-immune pathways. Evaluations of tailored preventive measures for individuals with anxiety/depression are needed to reduce CVD risk.

Posttraumatic stress disorder increases thrombosis risk: Evidence from a biobank data set.

Depression and anxiety are linked to deep venous thrombosis (DVT) and posttraumatic disorder (PTSD) increases risk of venous thromboembolism in women. However, the mechanisms underlying this relationship remain unknown. We hypothesized that PTSD would associate with increased DVT risk, that neuroimmune mechanisms would mediate the PTSD-DVT link, and that these associations would be stronger in women. This cohort study included N = 106 427 participants from a large biobank. PTSD and DVT were defined using ICD-10 codes. A subset (N = 1520) underwent imaging, from which we assessed stress-associated neural activity (SNA). High-sensitivity C-reactive protein (hs-CRP) levels and heart rate variability (HRV) were used as indicators of systemic inflammation and autonomic activity, respectively. Linear, logistic, and Cox regressions and mediation analyses were used to test our hypotheses. Of 106 427 participants, 4192 (3.9%) developed DVT. PTSD associated with increased DVT risk (HR [95% CI]: 1.66 [1.34, 2.07], p < .001), and this finding remained significant after adjustment for age, sex, and traditional DVT risk factors. When analyzed separately by sex, PTSD was significantly associated with DVT risk in women but not men. Further, heightened SNA and lower HRV mediated the effect of PTSD on DVT risk. Results suggest that individuals with PTSD are at increased risk for DVT, and that risk is higher in women. This relationship was partially driven by alterations in stress-associated neural activity and autonomic function, suggesting potential targets for preventive therapies. Future studies are needed to investigate whether intervening on PTSD-DVT mechanisms has downstream beneficial effects on DVT, especially among women.

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.

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.

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.

Body Composition, Coronary Microvascular Dysfunction, and Future Risk of Cardiovascular Events Including Heart Failure.

BACKGROUND: Body mass index (BMI) is a controversial marker of cardiovascular prognosis, especially in women. Coronary microvascular dysfunction (CMD) is prevalent in obese patients and a better discriminator of risk than BMI, but its association with body composition is unknown. OBJECTIVES: The authors used a deep learning model for body composition analysis to investigate the relationship between CMD, skeletal muscle (SM), subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT), and their contribution to adverse outcomes in patients referred for evaluation of coronary artery disease. METHODS: Consecutive patients (n = 400) with normal perfusion and preserved left ventricular ejection fraction on cardiac stress positron emission tomography were followed (median, 6.0 years) for major adverse events, including death and hospitalization for myocardial infarction or heart failure. Coronary flow reserve (CFR) was quantified as stress/rest myocardial blood flow from positron emission tomography. SM, SAT, and VAT cross-sectional areas were extracted from abdominal computed tomography at the third lumbar vertebra using a validated automated algorithm. RESULTS: Median age was 63, 71% were female, 50% non-White, and 50% obese. Compared with the nonobese, patients with obesity (BMI: 30.0-68.4 kg/m2) had higher SAT, VAT, and SM, and lower CFR (all P < 0.001). In adjusted analyses, decreased SM but not increased SAT or VAT was significantly associated with CMD (CFR <2; OR: 1.38; 95% CI: 1.08-1.75 per -10 cm2/m2 SM index; P < 0.01). Both lower CFR and SM, but not higher SAT or VAT, were independently associated with adverse events (HR: 1.83; 95% CI: 1.25-2.68 per -1 U CFR and HR: 1.53; 95% CI: 1.20-1.96 per -10 cm2/m2 SM index, respectively; P < 0.002 for both), especially heart failure hospitalization (HR: 2.36; 95% CI: 1.31-4.24 per -1 U CFR and HR: 1.87; 95% CI: 1.30-2.69 per -10 cm2/m2 SM index; P < 0.004 for both). There was a significant interaction between CFR and SM (adjusted P = 0.026), such that patients with CMD and sarcopenia demonstrated the highest rate of adverse events, especially among young, female, and obese patients (all P < 0.005). CONCLUSIONS: In a predominantly female cohort of patients without flow-limiting coronary artery disease, deficient muscularity, not excess adiposity, was independently associated with CMD and future adverse outcomes, especially heart failure. In patients with suspected ischemia and no obstructive coronary artery disease, characterization of lean body mass and coronary microvascular function may help to distinguish obese phenotypes at risk for cardiovascular events.

Health position paper and redox perspectives - Disease burden by transportation noise.

Transportation noise is a ubiquitous urban exposure. In 2018, the World Health Organization concluded that chronic exposure to road traffic noise is a risk factor for ischemic heart disease. In contrast, they concluded that the quality of evidence for a link to other diseases was very low to moderate. Since then, several studies on the impact of noise on various diseases have been published. Also, studies investigating the mechanistic pathways underlying noise-induced health effects are emerging. We review the current evidence regarding effects of noise on health and the related disease-mechanisms. Several high-quality cohort studies consistently found road traffic noise to be associated with a higher risk of ischemic heart disease, heart failure, diabetes, and all-cause mortality. Furthermore, recent studies have indicated that road traffic and railway noise may increase the risk of diseases not commonly investigated in an environmental noise context, including breast cancer, dementia, and tinnitus. The harmful effects of noise are related to activation of a physiological stress response and nighttime sleep disturbance. Oxidative stress and inflammation downstream of stress hormone signaling and dysregulated circadian rhythms are identified as major disease-relevant pathomechanistic drivers. We discuss the role of reactive oxygen species and present results from antioxidant interventions. Lastly, we provide an overview of oxidative stress markers and adverse redox processes reported for noise-exposed animals and humans. This position paper summarizes all available epidemiological, clinical, and preclinical evidence of transportation noise as an important environmental risk factor for public health and discusses its implications on the population level.

Amygdalar activity measured using FDG-PET/CT at head and neck cancer staging independently predicts survival.

IMPORTANCE: The mechanisms underlying the association between chronic stress and higher mortality among individuals with cancer remain incompletely understood. OBJECTIVE: To test the hypotheses that among individuals with active head and neck cancer, that higher stress-associated neural activity (ie. metabolic amygdalar activity [AmygA]) at cancer staging associates with survival. DESIGN: Retrospective cohort study. SETTING: Academic Medical Center (Massachusetts General Hospital, Boston). PARTICIPANTS: 240 patients with head and neck cancer (HNCA) who underwent 18F-FDG-PET/CT imaging as part of initial cancer staging. MEASUREMENTS: 18F-FDG uptake in the amygdala was determined by placing circular regions of interest in the right and left amygdalae and measuring the mean tracer accumulation (i.e., standardized uptake value [SUV]) in each region of interest. Amygdalar uptake was corrected for background cerebral activity (mean temporal lobe SUV). RESULTS: Among individuals with HNCA (age 59±13 years; 30% female), 67 died over a median follow-up period of 3 years (IQR: 1.7-5.1). AmygA associated with heightened bone marrow activity, leukocytosis, and C-reactive protein (P<0.05 each). In adjusted and unadjusted analyses, AmygA associated with subsequent mortality (HR [95% CI]: 1.35, [1.07-1.70], P = 0.009); the association persisted in stratified subset analyses restricted to patients with advanced cancer stage (P<0.001). Individuals within the highest tertile of AmygA experienced a 2-fold higher mortality rate compared to others (P = 0.01). The median progression-free survival was 25 months in patients with higher AmygA (upper tertile) as compared with 36.5 months in other individuals (HR for progression or death [95%CI], 1.83 [1.24-2.68], P = 0.001). CONCLUSIONS AND RELEVANCE: AmygA, quantified on routine 18F-FDG-PET/CT images obtained at cancer staging, independently and robustly predicts mortality and cancer progression among patients with HNCA. Future studies should test whether strategies that attenuate AmygA (or its downstream biological consequences) may improve cancer survival.

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.

Radionuclide Imaging of Heart-Brain Connections.

The heart and brain have a complex interplay wherein disease or injury to either organ may adversely affect the other. The mechanisms underlying this connection remain incompletely characterized. However, nuclear molecular imaging is uniquely suited to investigate these pathways by facilitating the simultaneous assessment of both organs using targeted radiotracers. Research within this paradigm has demonstrated important roles for inflammation, autonomic nervous system and neurohormonal activity, metabolism, and perfusion in the heart-brain connection. Further mechanistic clarification may facilitate greater clinical awareness and the development of targeted therapies to alleviate the burden of disease in both organs.