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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., (© 2024 Wiley Periodicals LLC.)

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 18 F-FDG-PET/CT imaging. SNA was measured as the ratio of amygdalar to cortical activity (AmygA C ). 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 AmygA C (standardized beta [95% CI]: 0.16 [0.04-0.27], p = .007, and 0.17 [0.05-0.29], p = .006, respectively). Furthermore, AmygA C 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 AmygA C , (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., (© 2024 Wiley Periodicals LLC.)

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., (Copyright © 2024 American Society of Nuclear Cardiology. Published by Elsevier Inc. All rights reserved.)

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., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

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 18 F-fluorodeoxyglucose positron emission tomography/computed tomographic imaging. Stress-related neural activity was measured as the ratio of resting amygdalar-to-cortical activity (AmygA C ). 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 AmygA C (standardized β: -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. AmygA C 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., Competing Interests: Funding Support and Author Disclosures This study is in part funded by National Institutes of Health (NIH) grants R56AR077187-01 and P01HL131478-05. This study was in part supported by NIH grants 1R01AR077187 (Dr Tawakol), P01HL131478 (Drs Tawakol and Fayad), K23HL151909 (Dr Osborne). Dr Osborne has received consulting fees from WCG Intrinsic Imaging, LLC, for unrelated work. Dr Choi has received support in part by funding from the National Institute of Mental Health (K08MH127413) and a NARSAD Brain and Behavior Foundation Young Investigator Award. Dr Smoller has received support for work outside the submitted research; is a member of the Scientific Advisory Board of Sensorium Therapeutics (with equity); has received an honorarium for an internal seminar at Tempus Labs and Biogen, Inc; and is PI of a study sponsored by 23andMe. Dr Tawakol has received grants from the National Institutes of Health, International Atomic Energy Agency, Osler/Harvard, and Lung Biotechnologies for work outside the submitted research. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

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/m 2 ) 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 cm 2 /m 2 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 cm 2 /m 2 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 cm 2 /m 2 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., Competing Interests: Funding Support and Author Disclosures This research was supported by a Lemann Cardiovascular Research Fellowship (Dr Souza); the National Institutes of Health (NIH) (U01CA320272, U01CA200468, and U10CA180821), the Lustgarten Foundation Dedicated Lab at Dana-Farber Cancer Institute, the Lustgarten Foundation and Stand Up To Cancer Pancreatic Cancer Collaborative, and the Hale Family Center for Pancreatic Cancer Research at Dana-Farber (Dr Rosenthal); a joint KL2/Catalyst Medical Research Investigator Training (CMeRIT) award from Harvard Catalyst and the Boston Claude D. Pepper Older Americans Independence Center (5P30AG031679-10) (Dr Divakaran); NIH K23HL151909 (Dr Osborne); and the Gilead Sciences Research Scholars Program in Cardiovascular Disease and NIH K23HL135438 (Dr Taqueti). Dr Blankenstein has received research support from Amgen Inc and Novartis Inc. Dr Osborne has received consulting fees from WCG Intrinsic Imaging for unrelated work. Dr Dorbala has received research grants from Pfizer, Attralus, and GE Healthcare; and consulting fees from Janssen, Pfizer, and GE Healthcare. Dr Di Carli has received research grants from Gilead Sciences and Spectrum Dynamics, and consulting fees from Bayer and Janssen. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The UDP glucuronosyltransferases (UGT) deactivate many therapeutics via glucuronidation while being required for clearance of normal metabolites and xenobiotics. There are 19 UGT enzymes categorized into UGT1A and UGT2B families based on sequence conservation. This presents a challenge in terms of targeting specific UGTs to overcome drug resistance without eliciting overt toxicity. Here, we identified for the first time that UGT1A4 is highly elevated in acute myeloid leukemia (AML) patients and its reduction corresponded to objective clinical responses. To develop inhibitors to UGT1A4, we leveraged previous NMR-based fragment screening data against the C-terminal domain of UGT1A (UGT1A-C). NMR and medicinal chemistry strategies identified novel chemical matter based on fragment compounds with the capacity to bind ∼20 fold more tightly to UGT1A-C (K d  ∼ 600 μM vs ∼30 μM). Some compounds differentially inhibited UGT1A4 versus UGT1A1 enzyme activity and restored drug sensitivity in resistant human cancer cells. NMR-based NOE experiments revealed these novel compounds recognised a region distal to the catalytic site suggestive of allosteric regulation. This binding region is poorly conserved between UGT1A and UGT2B C-terminal sequences, which otherwise exhibit high similarity. Consistently, these compounds did not bind to the C-terminal domain of UGT2B7 nor a triple mutant of UGT1A-C replaced with UGT2B7 residues in this region. Overall, we discovered a site on UGTs that can be leveraged to differentially target UGT1As and UGT2Bs, identified UGT1A4 as a therapeutic target, and found new chemical matter that binds the UGT1A C-terminus, inhibits glucuronidation and restores drug sensitivity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Individuals with posttraumatic stress disorder (PTSD) are at heightened risk for cardiovascular disease (CVD) compared to the general population. Inflammation and autonomic dysfunction are candidate mechanisms of CVD risk in PTSD; however, these mechanisms have not been well-characterised in the PTSD-CVD link. Further, these mechanisms may operate through altered stress-related neural activity (SNA). Yet, it remains unknown if changes in PTSD are associated with changes in CVD risk mechanisms. Objective: This manuscript describes the design and procedures of a pilot randomised controlled trial to assess the impact of a first-line treatment for PTSD (Cognitive Processing Therapy; CPT) versus waitlist control on mechanisms of CVD risk. Further, this study will test the hypothesis that CPT reduces CVD risk through its effects on inflammation and autonomic function and that these changes are driven by changes in SNA. Methods: Adults with PTSD and CVD risk ( N  = 30) will be randomised to CPT or waitlist control. Participants complete two laboratory visits (baseline and post-treatment) that include surveys, brain and peripheral imaging via 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), and resting measures of autonomic function. Primary outcomes include arterial inflammation and heart rate variability. Secondary outcomes include leukopoiesis (bone marrow uptake), heart rate, and blood pressure. The indirect effects of PTSD treatment on changes in inflammation and autonomic function through SNA will also be examined. Conclusions: This study seeks to characterise candidate neuroimmune mechanisms of the PTSD-CVD link to identify treatment targets and develop personalised interventions to reduce CVD events in PTSD populations. Trial registration: ClinicalTrials.gov identifier: NCT06429293..

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., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Hassan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Chronic stress associates with major adverse cardiovascular events (MACE) via increased stress-related neural network activity (SNA). Light/moderate alcohol consumption (AC l/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 AC l/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 18 F-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 AC l/m . Over a median follow-up of 3.4 years, 1,914 experienced MACE. AC l/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, AC l/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 AC l/m on MACE (log OR: -0.040; 95% CI: -0.097 to -0.003; P < 0.05). Further, AC l/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: AC l/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., Competing Interests: Funding Support and Author Disclosures This study was in part supported by National Institutes of Health grants 1R01AR077187 (to Dr Tawakol), 5P01HL131478 (to Dr Tawakol), K23HL151909 (to Dr Osborne). Dr Osborne has served as a consultant to WCG Intrinsic Imaging, LLC, unrelated to this work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

UDP-glucuronosyltransferases are the principal enzymes involved in the glucuronidation of metabolites and xenobiotics for physiological clearance in humans. Though glucuronidation is an indispensable process in the phase II metabolic pathway, UGT-mediated glucuronidation of most prescribed drugs (> 55%) and clinical evidence of UGT-associated drug resistance are major concerns for therapeutic development. While UGTs are highly conserved enzymes, they manifest unique substrate and inhibitor specificity which is poorly understood given the dearth of experimentally determined full-length structures. Such information is important not only to conceptualize their specificity but is central to the design of inhibitors specific to a given UGT in order to avoid toxicity associated with pan-UGT inhibitors. Here, we provide the 1 H, 13 C and 15 N backbone (~ 90%) and sidechain (~ 62%) assignments for the C-terminal domain of UGT2B17, which can be used to determine the molecular binding sites of inhibitor and substrate, and to understand the atomic basis for inhibitor selectivity between UGT2B17 and other members of the UGT2B subfamily. Given the physiological relevance of UGT2B17 in the elimination of hormone-based cancer drugs, these assignments will contribute towards dissecting the structural basis for substrate specificity, selective inhibitor recognition and other aspects of enzyme activity with the goal of selectively overcoming glucuronidation-based drug resistance., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

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., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Air pollution and noise exposures individually associate with major adverse cardiovascular events (MACE) via a mechanism involving arterial inflammation (ArtI); however, their combined impact on ArtI and MACE remains unknown. We tested whether dual (vs. one or neither) exposure associates with greater ArtI and MACE risk and whether MACE risk is mediated via ArtI., Methods: Individuals (N = 474) without active cancer or known cardiovascular disease with clinical 18 F-FDG-PET/CT imaging were followed for 5 years for MACE. ArtI was measured. Average air pollution (particulate matter ≤ 2.5 μm, PM 2.5 ) and transportation noise exposure were determined at individual residences. Higher exposures were defined as noise > 55 dBA (World Health Organization cutoff) and PM 2.5 ≥ sample median., Results: At baseline, 46%, 46%, and 8% were exposed to high levels of neither, one, or both pollutants; 39 experienced MACE over a median 4.1 years. Exposure to an increasing number of pollutants associated with higher ArtI (standardized β [95% CI: .195 [.052, .339], P = .008) and MACE (HR [95% CI]: 2.897 [1.818-4.615], P < .001). In path analysis, ArtI partially mediated the relationship between pollutant exposures and MACE (P < .05)., Conclusion: Air pollution and transportation noise exposures contribute incrementally to ArtI and MACE. The mechanism linking dual exposure to MACE involves ArtI., (© 2022. The Author(s) under exclusive licence to American Society of Nuclear Cardiology.)

The eukaryotic DNA replication fork is a hub of enzymes that continuously act to synthesize DNA, propagate DNA methylation and other epigenetic marks, perform quality control, repair nascent DNA, and package this DNA into chromatin. Many of the enzymes involved in these spatiotemporally correlated processes perform their functions by binding to proliferating cell nuclear antigen (PCNA). A long-standing question has been how the plethora of PCNA-binding enzymes exert their activities without interfering with each other. As a first step towards deciphering this complex regulation, we studied how Chromatin Assembly Factor 1 (CAF-1) binds to PCNA. We demonstrate that CAF-1 binds to PCNA in a heretofore uncharacterized manner that depends upon a cation-pi (π) interaction. An arginine residue, conserved among CAF-1 homologs but absent from other PCNA-binding proteins, inserts into the hydrophobic pocket normally occupied by proteins that contain canonical PCNA interaction peptides (PIPs). Mutation of this arginine disrupts the ability of CAF-1 to bind PCNA and to assemble chromatin. The PIP of the CAF-1 p150 subunit resides at the extreme C-terminus of an apparent long α-helix (119 amino acids) that has been reported to bind DNA. The length of that helix and the presence of a PIP at the C-terminus are evolutionarily conserved among numerous species, ranging from yeast to humans. This arrangement of a very long DNA-binding coiled-coil that terminates in PIPs may serve to coordinate DNA and PCNA binding by CAF-1.

Importance: Long-term disability after stroke is associated with socioeconomic status (SES). However, the reasons for such disparities in outcomes remain unclear., Objective: To assess whether lower SES is associated with larger admission infarct volume and whether initial infarct volume accounts for the association between SES and long-term disability., Design, Setting, and Participants: This cohort study was conducted in a prospective, consecutive population (n = 1256) presenting with acute ischemic stroke who underwent magnetic resonance imaging (MRI) within 24 hours of admission. Patients were recruited in Massachusetts General Hospital, Boston, from May 31, 2009, to December 31, 2011. Data were analyzed from May 1, 2019, until June 30, 2020., Main Outcomes and Measures: Initial stroke severity (within 24 hours of presentation) was determined using clinical (National Institutes of Health Stroke Scale [NIHSS]) and imaging (infarct volume by diffusion-weighted MRI) measures. Stroke etiologic subtypes were determined using the Causative Classification of Ischemic Stroke algorithm. Long-term stroke disability was measured using the modified Rankin Scale. Socioeconomic status was estimated using zip code-derived median household income and census block group-derived area deprivation index (ADI). Regression and mediation analyses were performed., Results: A total of 1098 patients had imaging and SES data available (mean [SD] age, 68.1 [15.7] years; 607 men [55.3%]). Income was inversely associated with initial infarct volume (standardized β, -0.074 [95% CI, -0.127 to -0.020]; P = .007), initial NIHSS (standardized β, -0.113 [95% CI, -0.171 to -0.054]; P < .001), and long-term disability (standardized β, -0.092 [95% CI, -0.149 to -0.035]; P = .001), which remained significant after multivariable adjustments. Initial stroke severity accounted for 64% of the association between SES and long-term disability (standardized β, -0.063 [95% CI, -0.095 to -0.029]; P < .05). Findings were similar when SES was alternatively assessed using ADI., Conclusions and Relevance: The findings of this cohort study suggest that lower SES is associated with larger infarct volumes on presentation. These SES-associated differences in initial stroke severity accounted for most of the subsequent disparities in long-term disability in this study. These findings shift the culpability for SES-associated disparities in poststroke disability from poststroke factors to those that precede presentation.

The control of RNA metabolism is an important aspect of molecular biology with wide-ranging impacts on cells. Central to processing of coding RNAs is the addition of the methyl-7 guanosine (m 7 G) "cap" on their 5' end. The eukaryotic translation initiation factor eIF4E directly binds the m 7 G cap and through this interaction plays key roles in many steps of RNA metabolism including nuclear RNA export and translation. eIF4E also stimulates capping of many transcripts through its ability to drive the production of the enzyme RNMT which methylates the G-cap to form the mature m 7 G cap. Here, we found that eIF4E also physically associated with RNMT in human cells. Moreover, eIF4E directly interacted with RNMT in vitro. eIF4E is only the second protein reported to directly bind the methyltransferase domain of RNMT, the first being its co-factor RAM. We combined high-resolution NMR methods with biochemical studies to define the binding interfaces for the RNMT-eIF4E complex. Further, we found that eIF4E competes for RAM binding to RNMT and conversely, RNMT competes for binding of well-established eIF4E-binding partners such as the 4E-BPs. RNMT uses novel structural means to engage eIF4E. Finally, we observed that m 7 G cap-eIF4E-RNMT trimeric complexes form, and thus RNMT-eIF4E complexes may be employed so that eIF4E captures newly capped RNA. In all, we show for the first time that the cap-binding protein eIF4E directly binds to the cap-maturation enzyme RNMT., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objectives: The authors aimed to study the sensitivity and specificity of exercise treadmill testing (ETT) in the diagnosis of coronary microvascular disease (CMD), as well as the prognostic implications of ETT results in patients with CMD., Background: ETT is validated to evaluate for flow-limiting coronary artery disease (CAD), however, little is known about its use for evaluating CMD., Methods: We retrospectively studied 249 consecutive patients between 2006 and 2016 who underwent ETT and positron emission tomography within 12 months. Patients with obstructive CAD or left ventricular systolic dysfunction were excluded. CMD was defined as a coronary flow reserve <2. Patients were followed for the occurrence of a first major adverse event (composite of death or hospitalization for myocardial infarction or heart failure)., Results: The sensitivity and specificity of a positive ETT to detect CMD were 34.7% (95% CI: 25.4%-45.0%) and 64.9% (95% CI: 56.7%-72.5%), respectively. The specificity of a positive ETT to detect CMD increased to 86.8% (95% CI: 80.3%-91.7%) when only classifying studies with ischemic electrocardiogram changes that lasted at least 1 minute into recovery as positive, although at a cost of lower sensitivity (15.3%; 95% CI: 8.8%-24.0%). Over a median follow-up of 6.9 years (IQR: 5.1-8.2 years), 30 (12.1%) patients met the composite endpoint, including 13 (13.3%) with CMD (n = 98). In patients with CMD, ETT result was not associated with the composite endpoint (P = 0.076)., Conclusions: Our data suggest limited sensitivity of ETT to detect CMD. However, a positive ETT with ischemic changes that persist at least 1 minute into recovery in the absence of obstructive CAD should raise suspicion for the presence of CMD given a high specificity. Further study is needed with larger patient sample sizes to assess the association between ETT results and outcomes in patients with CMD., Competing Interests: Funding Support and Author Disclosures Dr Divakaran has received a T32 postdoctoral training grant from the National Heart, Lung, and Blood Institute (T32 HL094301) and a joint KL2/Catalyst Medical Research Investigator Training (CMeRIT) award from Harvard Catalyst and the Boston Claude D. Pepper Older Americans Independence Center (5P30AG031679-10). Dr Zhou has received a T32 postdoctoral training grant from the National Heart, Lung, and Blood Institute (T32 HL094301). Dr Osborne has received a KL2/Catalyst Medical Research Investigator Training award (an appointed KL2 award) from Harvard Catalyst/The Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, National Institutes of Health Award KL2 TR002542). Dr Taqueti has received grant number K23 HL135438 from the National Heart, Lung, and Blood Institute. Dr Dorbala has received grant number R01 HL130563 from the National Heart, Lung, and Blood Institute. Dr Di Carli has received grant number R01 HL132021 from the National Heart, Lung, and Blood Institute. This work was conducted with support from Harvard Catalyst/The Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, National Institutes of Health Award UL 1TR002541) and financial contributions from Harvard University and its affiliated academic health care centers. The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University, and its affiliated academic health care centers, or the National Institutes of Health. Dr Osborne has served as a consultant for Intrinsic Imaging, LLC. Dr Dorbala is a member of an advisory board for General Electric Health Care. Dr Di Carli has received research grant support from Spectrum Dynamics and consulting fees from Sanofi and General Electric. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022. Published by Elsevier Inc.)

Background and Aims: Psoriasis is an immune-mediated inflammatory disease with increased risk of myocardial infarction. Preclinical studies in psoriasis models show an association between chronic inflammation and immune cell proliferation in the spleen and bone marrow (BM). We sought to test the hypothesis that splenic and BM 18 F-fluorodeoxyglucose ( 18 F-FDG) uptake is heightened in psoriasis and that higher uptake associates with systemic inflammation and subclinical atherosclerotic disease measures in this cohort., Methods: Multimodality imaging and biomarker assays were performed in 240 participants (210 with psoriasis and 30 healthy). Splenic and BM uptake was obtained using 18 F-FDG positron emission tomography/computed tomography (PET/CT). Coronary artery plaque characteristics including non-calcified burden (NCB) and lipid rich necrotic core (LRNC) were quantified using a dedicated software for CT angiography. All analyses were performed with StataIC 16 (Stata Corp., College Station, TX, USA)., Results: Splenic and BM 18 F-FDG uptake was increased in psoriasis (vs. healthy volunteers) and significantly associated with proatherogenic lipids, immune cells and systemic inflammation. Higher splenic 18 F-FDG uptake associated with higher total coronary burden (β = 0.37; p<0.001), NCB (β = 0.39; p<0.001), and LRNC (β = 0.32; p<0.001) in fully adjusted models. Similar associations were seen for BM 18 F-FDG uptake in adjusted models (β = 0.38; β = 0.41; β = 0.24; respectively, all p<0.001)., Conclusions: Heightened splenic and BM uptake of 18 F-FDG is associated with proatherogenic lipids, immune cells, inflammatory markers and coronary artery disease. These findings provide insights into atherogenic mechanisms in psoriasis and suggest that immune cell proliferation in the spleen and BM is associated with subclinical atherosclerosis., (Published by Elsevier B.V.)

Objective: To analyze opioid intake interference with psychological, well-being, and functional outcomes and medication tapering in patients with fibromyalgia admitted to the Mayo Clinic Pain Rehabilitation Program (MCPRP) in Florida., Patients and Methods: A retrospective study on MCPRP outcomes was conducted. We reviewed the health records of 150 patients with fibromyalgia who participated in the program from May 1, 2014, to May 1, 2015. All patients were asked to fill out a survey at admission to and dismissal from the program. Surveys contained questions from the numeric pain score, Multidimensional Pain Inventory (perceived life control and interference of pain subscales), Center for Epidemiological Studies-Depression Scale, Pain Catastrophizing Scale, 36-Item Short-Form Health Status Survey (general health perceptions subscale), and Pain Self-Efficacy Questionnaire. A medical record review identified categories and number of medications at program admission and dismissal. Patients were divided in 2 groups: those whose concomitant medication did not include opioids at admission (no opioids group) and those whose concomitant medication included opioids at admission (opioids group)., Results: By dismissal from the MCPRP, patients with fibromyalgia in the no opioids group had a significant ( P <.05) improvement in all the self-reported scores. Medication, including opioids, were effectively tapered at a substantially higher percentage in the opioids group., Conclusion: Benefit of the comprehensive pain rehabilitation program in patients with fibromyalgia was indicated by clinical improvements in pain severity, physical and emotional health, and functional capacity while successfully tapering medication. Opioid intake at admission may modify the program outcomes., (© 2021 THE AUTHORS.)

Objectives: The purpose of this study was to develop a risk prediction model for patients with nonobstructive CAD., Background: Among stable chest pain patients, most cardiovascular (CV) events occur in those with nonobstructive coronary artery disease (CAD). Thus, developing tailored risk prediction approaches in this group of patients, including CV risk factors and CAD characteristics, is needed., Methods: In PROMISE (Prospective Multicenter Imaging Study for Evaluation of Chest Pain) computed tomographic angiography patients, a core laboratory assessed prevalence of CAD (nonobstructive 1% to 49% left main or 1% to 69% stenosis any coronary artery), degree of stenosis (minimal: 1% to 29%; mild: 30% to 49%; or moderate: 50% to 69%), high-risk plaque (HRP) features (positive remodeling, low-attenuation plaque, and napkin-ring sign), segment involvement score (SIS), and coronary artery calcium (CAC). The primary end point was an adjudicated composite of unstable angina pectoris, nonfatal myocardial infarction, and death. Cox regression analysis determined independent predictors in nonobstructive CAD., Results: Of 2,890 patients (age 61.7 years, 46% women) with any CAD, 90.4% (n = 2,614) had nonobstructive CAD (mean age 61.6 yrs, 46% women, atherosclerotic cardiovascular disease [ASCVD] risk 16.2%). Composite events were independently predicted by ASCVD risk (hazard ratio [HR]: 1.03; p = 0.001), degree of stenosis (30% to 69%; HR: 1.91; p = 0.011), and presence of ≥2 HRP features (HR: 2.40; p = 0.008). Addition of ≥2 HRP features to: 1) ASCVD and CAC; 2) ASCVD and SIS; or 3) ASCVD and degree of stenosis resulted in a statistically significant improvement in model fit (p = 0.0036; p = 0.0176; and p = 0.0318; respectively). Patients with ASCVD ≥7.5%, any HRP, and mild/moderate stenosis had significantly higher event rates than those who did not meet those criteria (3.0% vs. 6.2%; p = 0.007)., Conclusions: Advanced coronary plaque features have incremental value over total plaque burden for the discrimination of clinical events in low-risk stable chest pain patients with nonobstructive CAD. This may be a first step to improve prevention in this cohort with the highest absolute risk for CV events., Competing Interests: Funding Support and Author Disclosures The PROMISE trial was supported by grants from the National Heart Lung and Blood Institute, Bethesda, Maryland: R01HL098237, R01HL098236, R01HL098305, and R01HL098235. Dr Taron is funded by the Deutsche Forschungsgemeinschaft (German Research Foundation; TA 1438/1-2); and is on the Speakers Bureau for Siemens Healthcare, unrelated to this work. Dr Osborne has received grant support from the National Institutes of Health (KL2TR002542) and Intrinsic Imaging, for unrelated work. Dr Meyersohn has received support from the National Institutes of Health/National Heart, Lung, and Blood Institute (T32 HL076136). Dr Lu has received consulting fees with PQBypass, a research grant from the Nvidia Corporation Academic Program, work as a co-investigator on research funded by AstraZeneca and Kowa, and grant support from the American Heart Association Precision Medicine Institute (18UNPG34030172) and the Harvard University Center for AIDS Research (NIH/NIAID 5P30AI060354-14). Dr Ferencik has received grant support from the American Heart Association (13FTF16450001). Dr Pagidipati has received research grants from Amgen, AstraZeneca, Baseline Study, Boehringer Ingelheim, Duke Clinical Research Institute, Eli Lilly & Company, Novo Nordisk Pharmaceutical Company, Regeneron Pharmaceuticals, Sanofi, and Verily Sciences Research Company; and consulting fees from AstraZeneca, Boehringer Ingelheim, Esperion Therapeutics, Eli Lilly & Company, and Novo Nordisk Pharmaceutical Company. Dr Douglas has received a research grant from HeartFlow. Dr Hoffmann has received a grant from the National Institutes of Health (K24HL113128), research support on behalf of the Massachusetts General Hospital from Duke University, HeartFlow, Kowa Company, and MedImmune/AstraZeneca; and consulting fees from Duke University and Recor Medical unrelated to this research. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

The human UDP-glucuronosyltransferase (UGT) family of enzymes catalyze the covalent addition of glucuronic acid to a wide range of compounds, generally rendering them inactive. Although important for clearance of environmental toxins and metabolites, UGT activation can lead to inappropriate glucuronidation of therapeutics underlying drug resistance. Indeed, 50% of medications are glucuronidated. To better understand this mode of resistance, we studied the UGT2B7 enzyme associated with glucuronidation of cancer drugs such as Tamoxifen and Sorafenib. We report 1 H,  13 C and 15 N backbone (> 90%) and side-chain assignments (~ 78% completeness according to CYANA) for the C-terminal domain of UGT2B7 (UGT2B7-C). Given the biomedical importance of this family of enzymes, our assignments will provide a key tool for improving understanding of the biochemical basis for substrate selectivity and other aspects of enzyme activity. This in turn will inform on drug design to overcome UGT-related drug resistance., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

Accumulating evidence from human-based research has highlighted that the prevalent one-size-fits-all approach for neural and behavioral interventions is inefficient. This approach can benefit one individual, but be ineffective or even detrimental for another. Studying the efficacy of the large range of different parameters for different individuals is costly, time-consuming and requires a large sample size that makes such research impractical and hinders effective interventions. Here an active machine learning technique is presented across participants-personalized Bayesian optimization (pBO)-that searches available parameter combinations to optimize an intervention as a function of an individual's ability. This novel technique was utilized to identify transcranial alternating current stimulation (tACS) frequency and current strength combinations most likely to improve arithmetic performance, based on a subject's baseline arithmetic abilities. The pBO was performed across all subjects tested, building a model of subject performance, capable of recommending parameters for future subjects based on their baseline arithmetic ability. pBO successfully searches, learns, and recommends parameters for an effective neurointervention as supported by behavioral, simulation, and neural data. The application of pBO in human-based research opens up new avenues for personalized and more effective interventions, as well as discoveries of protocols for treatment and translation to other clinical and non-clinical domains., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: RCK consults, and serves on the scientific advisory boards for Neuroelectrics and Innosphere. The UK Patent Application Number 2000874.4 (“method for obtaining personalized parameters for transcranial stimulation, transcranial system, method of applying transcranial stimulation”) was filed by NERvB, TLR, VN, and RCK. This patent covers the method of obtaining personalized parameters for transcranial stimulation as described in this manuscript.

Background: Chronic transportation noise exposure associates with cardiovascular events through a link involving heightened stress-associated neurobiological activity (as amygdalar metabolic activity, AmygA) on 18 F-fluorodeoxyglucose positron emission tomography/computed tomography ( 18 F-FDG-PET/CT). Increased AmygA also associates with greater visceral adipose tissue (VAT) and type 2 diabetes mellitus (DM). While relationships between noise exposure and VAT and DM have been reported, the underlying mechanisms remain incompletely understood. We tested whether: (1) transportation noise exposure associates with greater (a) baseline and gains in VAT and (b) DM risk, and (2) heightened AmygA partially mediates the link between noise exposure and these metabolic diseases., Methods: VAT was measured in a retrospective cohort (N = 403) who underwent clinical 18 F-FDG-PET/CT. AmygA was measured in those with brain imaging (N = 238). Follow-up VAT was remeasured on available imaging (N = 67). Among individuals (N = 224) without baseline DM, incident DM was adjudicated over 2 years from clinical records. Noise (24-h average) was modeled at each individual's home address. Linear regression, survival, and mediation analyses were employed., Results: Higher noise exposure (upper tertile vs. others) associated with greater: baseline VAT (standardized β [95% confidence interval (CI)]= 0.230 [0.021, 0.438], p = 0.031), gains in VAT (0.686 [0.185, 1.187], p = 0.008 adjusted for baseline VAT), and DM (hazard ratio [95% CI]=2.429 [1.031, 5.719], p = 0.042). The paths of: ↑noise exposure→↑AmygA→↑baseline VAT and ↑noise exposure→↑AmygA→↑subsequent DM were significant (p < 0.05)., Conclusions: Increased transportation noise exposure associates with greater VAT and DM. This relationship is partially mediated by stress-associated neurobiological activity. These findings suggest altered neurobiology contributes to noise exposure's link to metabolic diseases., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Positron emission tomography (PET) imaging can yield unique mechanistic insights into the pathophysiology of atherosclerosis. 18 F-fluorodeoxyglucose ( 18 F-FDG), a radiolabeled glucose analog, is retained by cells in proportion to their glycolytic activity. While 18 F-FDG accumulates within several cell types in the arterial wall, its retention correlates with macrophage content, providing an index of arterial inflammation (ArtI) which predicts subsequent cardiovascular disease (CVD) events. Furthermore, 18 F-FDG-PET imaging allows the simultaneous assessment of metabolic activity in several tissues (e.g., brain, bone marrow) and is performed in conjunction with cross-sectional imaging that enables multi-organ structural assessments. Accordingly, 18 F-FDG-PET/computed tomography (CT) imaging facilitates evaluation of disease pathways that span multiple organ systems. Within this paradigm, 18 F-FDG-PET/CT imaging has been implemented to study the mechanism linking chronic stress to CVD. To evaluate this, stress-associated neural activity can be quantified (as metabolic activity of the amygdala (AmygA)), while leukopoietic activity, ArtI, and coronary plaque burden are assessed concurrently. Such simultaneous quantification of tissue structures and activities enables the evaluation of multi-organ pathways with the aid of mediation analysis. Using this approach, multi-system 18 F-FDG-PET/CT imaging studies have demonstrated that chronically heightened stress-associated neurobiological activity promotes leukopoietic activity and systemic inflammation. This in turn fuels more ArtI and greater non-calcified coronary plaque burden, which result in more CVD events. Subsequent studies have revealed that common stressors, such as chronic noise exposure and income disparities, drive the front end of this pathway to increase CVD risk. Hence, multi-tissue multimodality imaging serves as a powerful tool to uncover complex disease mechanisms.

Aims: Activity in the amygdala, a brain centre involved in the perception of and response to stressors, associates with: (i) heightened sympathetic nervous system and inflammatory output and (ii) risk of cardiovascular disease. We hypothesized that the amygdalar activity (AmygA) ratio is heightened among individuals who develop Takotsubo syndrome (TTS), a heart failure syndrome often triggered by acute stress. We tested the hypotheses that (i) heightened AmygA precedes development of TTS and (ii) those with the highest AmygA develop the syndrome earliest., Methods and Results: Individuals (N=104, median age 67.5 years, 72% female, 86% with malignancy) who underwent clinical 18 F-FDG-PET/CT imaging were retrospectively identified: 41 who subsequently developed TTS and 63 matched controls (median follow-up 2.5 years after imaging). AmygA was measured using validated methods. Individuals with (vs. without) subsequent TTS had higher baseline AmygA (P=0.038) after adjusting for TTS risk factors. Further, AmygA associated with the risk for subsequent TTS after adjustment for risk factors [standardized hazard ratio (95% confidence interval): 1.643 (1.189, 2.270), P=0.003]. Among the subset of individuals who developed TTS, those with the highest AmygA (>mean + 1 SD) developed TTS ∼2 years earlier after imaging vs. those with lower AmygA (P=0.028)., Conclusion: Higher AmygA associates with an increased risk for TTS among a retrospective population with a high rate of malignancy. This heightened neurobiological activity is present years before the onset of TTS and may impact the timing of the syndrome. Accordingly, heightened stress-associated neural activity may represent a therapeutic target to reduce stress-related diseases, including TTS., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Objectives: In the general population, the lower socioeconomic status (SES) associates with greater systemic and arterial inflammation and a greater risk of cardiovascular disease. Because arterial inflammation is heightened in individuals living with HIV, we tested the hypothesis that SES associates with arterial inflammation in this population., Settings: Prospective cohort study., Methods: Men living with HIV were recruited. Arterial inflammation and leukopoietic activity (ie, bone marrow activity) were measured using 18F-fluorodeoxyglucose positron emission tomography/computed tomography. Zip code-level SES measures were derived from the US Census Bureau. Linear regression and mediation analyses were used to assess associations between SES, arterial inflammation, leukopoietic activity, C-reactive protein (CRP), and interleukin-6., Results: Thirty-nine virologically suppressed men living with HIV were studied (mean ± SD age 50.5 ± 11.1 years). The median CD4 count was 663 cells/mm3 (interquartile range: 399-922); 82% were receiving antiretroviral therapies. Local median income inversely associated with arterial inflammation [standardized β (95% confidence interval): -0.42 (-0.76 to -0.08)] after adjusting for age, Framingham risk score, statin use, antiretroviral use, and nadir CD4 count. The high-school graduation rate independently associated with arterial inflammation [-0.45 (-0.78 to -0.12)] and CRP [-0.49 (-0.86 to -0.012)]. Mediation analysis demonstrated the impact of SES on arterial inflammation was partially mediated by heightened circulating inflammatory levels: ↓SES (as high school graduation rate) →↑CRP →↑arterial inflammation accounting for 44% of the total effect (P < 0.05)., Conclusion: In individuals living with HIV, lower SES independently associated with higher leukopoietic activity, circulating markers of inflammation, and arterial inflammation. Furthermore, the link between SES and arterial inflammation was mediated by increased systemic inflammation., Competing Interests: M.T.O. has received consulting fees from Intrinsic Imaging, LLC for external work. P.Y.H. has received honoraria unrelated to the topic of this paper from Gilead and Merck. The other authors have no conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: While growing evidence suggests a link between periodontal disease (PD) and cardiovascular disease (CVD), the independence of this association and the pathway remain unclear. Herein, we tested the hypotheses that: (1) inflammation of the periodontium (PD inflammation ) predicts future CVD independently of disease risk factors shared between CVD and PD, and (2) the mechanism linking the two diseases involves heightened arterial inflammation., Methods: 18 F-fluorodeoxyglucose positron emission tomography/computed tomography ( 18 F-FDG-PET/CT) imaging was performed in 304 individuals (median age 54 years; 42.4% male) largely for cancer screening; individuals without active cancer were included. PD inflammation and arterial inflammation were quantified using validated 18 F-FDG-PET/CT methods. Additionally, we evaluated the relationship between PD inflammation and subsequent major adverse cardiovascular events (MACE) using Cox models and log-rank tests., Results: Thirteen individuals developed MACE during follow-up (median 4.1 years). PD inflammation associated with arterial inflammation, remaining significant after adjusting for PD and CVD risk factors (standardized β [95% CI]: 0.30 [0.20-0.40], P < 0.001). PD inflammation predicted subsequent MACE (standardized HR [95% CI]: 2.25 [1.47 to 3.44], P <0.001, remaining significant in multivariable models), while periodontal bone loss did not. Furthermore, mediation analysis suggested that arterial inflammation accounts for 80% of the relationship between PD inflammation and MACE (standardized log odds ratio [95% CI]: 0.438 [0.019-0.880], P = 0.022)., Conclusion: PD inflammation is independently associated with MACE via a mechanism that may involve increased arterial inflammation. These findings provide important support for an independent relationship between PD inflammation and CVD., (© 2021 American Academy of Periodontology.)

Aims: Air pollution [i.e. particulate matter with diameter <2.5 μm (PM2.5)] is a risk factor for major adverse cardiovascular events (MACE). While PM2.5 promotes leucopoiesis and atherosclerotic inflammation in experimental models, it is unknown whether this occurs in humans. We tested in humans (a) whether PM2.5 associates with higher leucopoietic tissue activity and arterial inflammation (ArtI), (ii) whether these associations persist after accounting for the effects of potential confounders including socioeconomics, traffic noise, and risk factors, and (iii) whether these tissue effects mediate the association between air pollution and MACE., Methods and Results: Individuals (N = 503) without cardiovascular disease (CVD) or active malignancy underwent 18 F-fluorodeoxyglucose positron emission tomography/computed tomography. Major adverse cardiovascular event was adjudicated over 5 years of follow-up. Leucopoietic tissue activity (in bone marrow and spleen) as well as ArtI were measured. Annual PM2.5 levels were assessed at each individual's home address. At baseline, higher PM2.5 associated with increased leucopoietic activity [standardized (95% CI): 0.129 (0.042, 0.215), P = 0.004] as well as ArtI [0.088 (0.006, 0.171), P = 0.036] after adjusting for CVD risk factors. Over a median 4.1 years, 40 individuals experienced MACE. PM2.5 exposure associated with MACE [Cox HR (95% CI): 1.404 (1.135, 1.737), P = 0.002], remaining significant after adjustment for CVD risk factors and other potential confounders. Mediation analysis demonstrated that increased leucopoietic activity and ArtI serially mediate the link between PM2.5 exposure and MACE., Conclusions: Higher air pollution exposure associates with heightened leucopoietic activity and ArtI and independently predicts MACE through a biological pathway that includes higher leucopoietic activity and ArtI in series., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Stress is a pervasive component of the human experience. While often considered an adversity to be ignored, chronic stress has important pathological consequences, including cardiovascular disease (CVD). Stress also increases the prevalence and severity of several CVD risk factors, including hypertension, diabetes mellitus, and obesity. Yet even after adjustment, stress' attributable CVD risk is similar to those risk factors, suggesting it is a particularly potent contributor. Nevertheless, there has been insufficient study of mechanisms linking stress to CVD or of methods to attenuate stress' pathological impact. This review covers the current concepts of how stress impacts CVD and emerging approaches to mitigate stress-attributable CVD risk.